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Psychoneuroimmunology: Conditioning and Stress



The acquisition and extinction of the conditioned suppression or enhancement of one or another parameter of antigen-specific and nonspecific defense system responses have been documented in different species under a variety of experimental conditions. Similarly, stressful stimulation influences antigen-specific as well as nonspecific reactions. Moreover, both conditioning and stressful stimulation exert biologically meaningful effects in the sense that they can alter the development and/or progression of what are presumed to be immunologically mediated pathophysiologic processes. These are highly reproducible phenomena that illustrate a functional relationship between the brain and the immune system. However, the extent to which one can generalize from one stressor to another or from one parameter of immunologic reactivity to another is limited. Few generalizations are possible because the direction and/or magnitude of the effects of conditioning and "stress" in modulating immune responses clearly depend on the quality and quantity of the behavioral interventions, the quality and quantity of antigenic stimulation, the temporal relationship between behavioral and antigenic stimulation, the nature of the immune response and the immune compartment in which it is measured, the time of sampling, a variety of host factors (e.g. species, strain, age, sex), and interactions among these several variables. It seems reasonable to assume that the immunologic effects of behaviorally induced neural and endocrine responses depend on (interact with) the concurrent immunologic events upon which they are superimposed. Conversely, the efficacy of immunologic defense mechanisms seems to depend on the neuroendocrine environment on which they are superimposed. We seek to determine when and what immunologic (or neuroendocrine) responses could be affected by what neuroendocrine (or immunologic) circumstances. We therefore need studies that provide a parametric analysis of the stimulus conditions, the neuroendocrine and/or immunologic state upon which they are superimposed, and the responses that are being sampled. The neural or neuroendocrine pathways involved in the behavioral alteration of immune responses are not yet known. Both conditioning and stressor-induced effects have been hypothesized to result from the action of adrenocortical steroids, opioids, and catecholamines, among others. Indeed, all of these have been implicated in the mediation of some immunologic effects observed under some experimental conditions. We assume that different conditioning and stressful environmental circumstances induce different constellations of neuroendocrine responses that constitute the milieu within which ongoing immunologic reactions and the response to immunologic signals occur.(ABSTRACT TRUNCATED AT 400 WORDS)
Annu. Rev. Psychol. 1993. 44:53~5
Copyright © 1993 by Annual Reviews Inc. All rights reserved
Robert Ader and Nicholas Cohen
Department of Psychiatry and Microbiology and Immunology, University of Rochester
School of Medicine and Dentistry, Rochester, New York 14642
KEYWORDS: psychoneuroimmunology, conditioning, stress
INTRODUCTION ..................................................................................................................... 53
CONDITIONED MODULATION OF IMMUNITY ................................................................ 54
Effects of Conditioning on Humoral and Cell-Mediated Immunity ..................... 55
Effects of Conditioning on Nonimmunologically Specific Reactions ..................
Antigen as Unconditioned Stimulus .....................................................................
Biologic Impact of Conditioned Changes in Immunity ........................................ 61
Conditioning in Human Subjects .........................................................................
STRESS AND IMMUNITY ......................................................................................................63
Effects of Stress on Disease ..................................................................................
Effects of Stress on Humoral and Cell-Mediated Immunity ................................
Effects of Stress on Nonimmunologically Specific Reactions ..............................
SUMMARY .............................................................................................................................. 76
During the past 10-15 years, psychoneuroimmunology--the study of the in-
teractions among behavior, neural and endocrine function, and immune pro-
cesses--has developed into a bona fide field of interdisciplinary research
(Ader 1981a, 1991a). Previously unknown and unsuspected connections be-
tween the brain and the immune system provide a foundation for the now
numerous observations both (a) that the manipulation of neural and endocrine
functions alters immune responses, and the antigenic stimulation that induces
an immune response results in changes in neural and endocrine function and
(b) that behavioral processes are capable of influencing immunologic reactiv-
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ity and, conversely, the immune status of an organism has consequences for
behavior. This new research indicates that the nervous and immune systems,
the two most complex systems involved in the maintenance of homeostasis,
represent an integrated mechanism contributing to the adaptation of the indi-
vidual and the species. Psychoneuroimmunology emphasizes the functional
significance of the relationship between these systems--not in place of, but in
addition to the more traditional disciplinary analysis of the mechanisms gov-
erning functions within a single system.
The range of phenomena that bears on the relationship between behavior
and immunity is quite broad, and no attempt will be made to provide even a
cursory summary of all this literature. We focus here on animal studies of the
effects of conditioning and stress in the modulation of immune function. There
are several more or less programmatic lines of research in humans that the
reader may wish to explore. These deal with the immunologic correlates of
emotional states (primarily depression), personality traits as modulators
immune function, and the effects of stress on immune function. Few general-
izations are possible based on currently available data. Although there is no
definitive evidence for the implied chain of events, the hypothesis that im-
mune function may mediate the effects of psychosocial factors on the suscepti-
bility to or progression of some disease processes remains tenable. We confine
this review, however, to the experimental literature on the modulation of
immunity by stress and conditioning. Other recent reviews (e.g.S. Cohen
Williamson 1991; Geiser 1989; Kemeny et al 1992; O’Leary 1990) have dealt
with personality and emotional factors and immunity and/or disease. Some of
these have included an introductory outline of the immune system; an exten-
sive treatment of immune function can be found in any of several recent texts
(e.g. Stites & Ten" 1991).
Immune responses, like other physiological processes, can be modified by
classical conditioning. Conditioned modulation of host defense mechanisms
and antigen-specific immune responses were first explored by Russian investi-
gators and followed the Pavlovian conditioning principles and procedures of
the day (Metal’nikov & Chorine 1926, 1928). Typically, multiple pairings of
conditioned stimulus (CS; e.g. heat, tactile stimulation) were paired with injec-
tions of a foreign protein, the unconditioned stimulus (UCS); subsequent
presentation of the CS alone was reported to elicit conditioned increases both
in a variety of nonspecific defense responses and in antibody production.
There were English language reviews of this literature (Hull 1934; Kopeloff
1941), but they apparently attracted little attention, probably owing to the
nascent state of immunology at the time and to the fact that by today’s
standards most of these early animal experiments were inadequately de-
scribed, poorly designed, lacked appropriate control groups, and constituted
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little more than preliminary observations. Although the data on specific anti-
body responses were not convincing, the studies of nonspecific cellular events
(e.g. changes in leukocyte number, phagocytosis, inflammatory responses)
were consistent and provided provocative evidence that conditioning could
modulate host defenses. A detailed review (and some reanalyses) of these data
was provided by Ader (1981 b).
Effects of Conditioning on Humoral and Cell-Mediated
One of the hallmarks of the immune system’s defense of the organism against
foreign, "nonself" material (antigens) is its specificity--its ability to recognize
precisely and then eliminate only the antigens it has confronted. These activi-
ties are carried out by a variety of white blood cells (leukocytes). Prominent
among these are T and B lymphocytes that are capable of clonal proliferation
in response to antigens and retaining the "memory" of that encounter. Hu-
moral or antibody-mediated immunity involves the exposure of antigens to
bone marrow-derived B cells. These cells effect the ultimate production of
antibodies that protect the organism against extracellular microorganisms and
reinfection. Cell-mediated immunity is provided by thymus-derived T cells
that protect against intracellular parasitic and viral infections. An integrated
immune response to antigens, however, involves complex interactions among
specialized subpopulations of T cells (i.e. helper, suppressor, cytotoxic),
cells, other white blood cells such as macrophages, and substances (cytokines)
that are secreted by activated leukocytes. A variety of techniques have been
developed to measure these cellular interactions in vitro. The essence of psy-
choneuroimmunology, however, is the recognition that in vivo these reactions
occur within a neuroendocrine milieu that is demonstrably sensitive to the
organism’s perception of and adaptation to events occurring in its environ-
HUMORAL IMMUNITY Current interest in conditioned changes in immunologic
reactivity began with a study by Ader & Cohen (1975). Using a taste aversion
conditioning paradigm, a saccharin-flavored drinking solution, the CS, was
paired with an injection of cyclophosphamide (CY), an immunosuppressive
UCS. All rats were subsequently immunized with sheep red blood cells (SRBC).
Antibody titers were measured in conditioned animals that were injected with
CY on the day of immunization (to define the unconditioned immunosuppress-
ive effects of CY), in conditioned animals that were not reexposed to the CS (to
assess the influence of prior conditioning and the residual effects of CY), and
in conditioned animals that were reexposed to the CS on the day of immuniza-
tion and/or three days later (the critical experimental group). Subgroups
(nonconditioned) animals were injected with CY following the drinking of plain
water before immunization and were subsequently provided with the presum-
ably neutral saccharin solution whenever a comparable subgroup of conditioned
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animals received saccharin. A placebo-treated group was injected with vehicle
after consuming saccharin or water before immunization and was exposed to
saccharin after immunization. As expected, conditioned animals showed an
aversion to the saccharin solution that had been paired with CY. Conditioned
animals that were reexposed to the CS at the time of, and/or three days after,
immunization also showed an attenuated anti-SRBC antibody response relative
either to conditioned animals that were not reexposed to saccharin or to
nonconditioned animals that were similarly exposed to saccharin. These results
were interpreted as reflecting a conditioned immunosuppressive response. The
acquisition and the experimental extinction of a conditioned suppression and/or
enhancement of antibody- and cell-mediated immune responses as well as
nonspecific host defenses have now been observed under a variety of experi-
mental conditions. Only a brief overview of this research is provided here; more
detailedreviews are available elsewhere (Ader & Cohen 1985, 1991).
In the conditioned taste aversion paradigm, animals learn to avoid flavored
solutions previously paired with the noxious or illness-inducing effects of a
variety of (pharmacologic) agents; that is, they reduce their consumption
the CS solution. Therefore, to obviate the conflict ("stress") induced by having
either to drink a solution paired with illness or to remain thirsty--and to
equate total fluid consumption among differentially treated animals~ondi-
tioning can be assessed with a two-bottle preference procedure that permits the
animal to choose between plain water and the flavored CS solution. Under
these conditions, conditioned alterations of humoral (e.g. Ader et al 1982;
Bovbjerg et al 1987b; N. Cohen et al 1979) and cell-mediated (Bovbjerg et
1982, 1984) immune responses are still obtained. The available literature
reveals no consistent relationship between conditioned behavioral (aversive)
responses and conditioned immune changes in the taste aversion learning
paradigm; taste aversions can be expressed without concomitant changes in
humoral immunity, and conditioned changes in immune function can be ob-
tained without observable conditioned avoidance responses (Ader & Cohen
1975; Ader et al 1987; Bovbjerg et al 1987b; Gorczynski 1987; Gorczynski et
al 1984; Rogers et al 1976; Schulze et al 1988; Wayner et al 1978). Moreover,
reexposure to the CS before rather than after immunization with SRBC also
depresses in vivo antibody production (Ader et al 1982; Schulze et al 1988;
Kusnecov et al 1988). The latter results suggest that an antigen-activated
immune system is not necessary for the conditioning of an immunosuppress-
ive response.
Conditioned immunomodulatory effects are not confined to the use of CY
or the taste aversion conditioning situation. Conditioned changes in various
parameters of immunologic reactivity have been observed using other im-
munomodulating substances (e.g. Ader & Cohen 1981; King et al 1987;
Kusnecov et al 1983; see also Hiramoto et al 1987; Husband et al 1987). It is
not even necessary to use immunopharmacologic agents as UCSs; evidence
for a conditioned suppression of antibody-mediated responses has been ob-
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tained using electric shock as the UCS (Sato et al 1984; Zalcman et al 1989,
There have been a few studies in which there were no observable condi-
tioned effects (Krank & MacQueen 1988; MacQueen & Siegel 1989). For
theoretical reasons (see Eikelboom & Stewart 1982), these experiments were
conducted with the expectation of observing "paradoxical" or compensatory
conditioned responses (responses opposite in direction to the unconditioned
response). In conditioned animals reexposed to a CS previously paired with
CY, the anti-SRBC antibody response was higher than the response of condi-
tioned animals that were not reexposed to the CS and the response of animals
that experienced unpaired CS-UCS presentations, but the responses of condi-
tioned animals reexposed to the CS did not differ from those of a saline-treated
control group. Such results may permit one to infer the existence of a condi-
tioned enhancement of antibody production based on the failure to observe
immunosuppression, but, as the investigators acknowledge, no direct evidence
of compensatory conditioning was obtained. There is no obvious explanation
for the difference between these results and those in the rest of the literature on
conditioned immunologic changes.
Evidence for the existence of the compensatory conditioning of host de-
fense reactions, however, can be derived from studies on the role of condition-
ing in the development of pharmacological tolerance to repeated injections of
polyinosinic-polycytidylic acid (poly I:C; Dyck et al 1986, 1987). In keeping
with a conditioning analysis of the development of tolerance to some other
pharmacologic agents (Siegel 1983), tolerance to the enhancing effects of poly
I:C on natural killer cell activity is abrogated by unreinforced exposures to the
CS; preexposure to the CS interferes with the development of tolerance; and
tolerance is attenuated when poly I:C is injected in the absence of environmen-
tal cues previously paired with injections of the drug.
CELL-MEDIATED IMMUNITY The immunosuppressive effects of CY can also be
used to condition changes in cell-mediated responses. In the studies by Bovbjerg
et al (1982, 1984), (Lewis x Brown Norwegian)Fl rats were injected with Lewis
strain spleen cells to induce a local graft vs host (GvH) response. The basic
experimental protocol used by Ader & Cohen (1975) was modified so that: (a)
there was a 7-week interval between conditioning of the FI hybrid hosts and
injecting them with donor cells (at which time there were no detectable residual
effects of CY), and (b) experimental animals were reexposed to the CS in
context of reexposure to a minimally effective injection of CY. (The Lewis
Brown Norwegian)F1 rats were first conditioned by pairing saccharin consump-
tion and CY and were subsequently injected ("grafted") with splenic leukocytes
When splenic leukocytes from an inbred strain of Lewis rats are injected into the footpad of
hybrid (Lewis x Brown Norwegian)F~ rats, the grafted cells recognize the host as "foreign," and
local inflammatory reaction (the GvH response) ensues and can be measured by weighing the
popliteal lymph node that drains the injection site.
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from Lewis strain donors. On the day of grafting and on the following two days
they were reexposed to the CS; on the day after grafting they were also given a
low dose injection of CY. While low-dose injections of CY on Days 0, 1, and
2 dramatically suppressed the local GvH response, a single injection on Day l
caused only a modest decrease in the response. However, a single low-dose
injection of CY plus reexposure to the CS previously paired with CY signifi-
cantly suppressed the GvH response relative to control groups that received only
the single low-dose injection of CY. As expected, unreinforced exposures to the
CS during the 7-week interval between conditioning and induction of the GvH
response resulted in extinction of the conditioned immunosuppressive response.
Experimental extinction, one hallmark of a conditioned response, has also been
reported for other conditioned immunologic effects (Dyck et al 1986;
Gorczynski et al 1982; see also Lysle et al 1988).
Cyclophosphamide can enhance as well as suppress immunologic reactiv-
ity. In the case of a delayed-type hypersensitivity (DTH)
reaction to SRBC,
low-dose treatment with CY at the time of sensitization can enhance DTH in
response to a subsequent challenge with the same antigen (Turk & Parker
1982); CY treatment of sensitized animals just before antigenic challenge
decreases the DTH response (Gill & Liew 1978; Rodinone et al 1983). Al-
though CY decreases the DTbI reaction to an initial antigenic challenge, the
response to subsequent challenges is enhanced (Bovbjerg et al 1986).
Bovbjerg et al (1987a) did not observe any conditioning effects when sensi-
tized animals, previously conditioned with CY, were reexposed to the CS
before their initial challenge. However, reexposing conditioned animals to the
CS before two subsequent antigenic challenges resulted in enhanced DTH
responses. The conditioned enhancement could be a consequence of a selec-
tive conditioned immunosuppressive effect on suppressor cells (Gill & Liew
1978; Mitsuoka et al 1979). Another drug, levamisole, has been purported to
selectively depress cytotoxic/suppressor T cells. Thus, the conditioned eleva-
tion of the T-helper:T-suppressor-subset ratio in animals reexposed to a CS
previously paired with levamisole (Husband et al 1987) could be the phenom-
enological expression of a conditioned immunosuppressive response. Such an
interpretation would be consonant with data suggesting that T cell-dependent
reactions are especially sensitive to conditioning.
As in the case of antibody-mediated immune responses, conditioned
changes involving cell-mediated immunity are not confined to the use of the
taste aversion conditioning model. Mice exposed to a novel environment plus
a distinctive taste in conjunction with rotation on a turntable (the UCS) show
decreased ability to reject allogeneic skin grafts when reexposed to the com-
pound CS at the time of and following the antigenic challenge (Gorczynski
1992). In addition, when conditioned females (mated with nonconditioned
DTH is an in vivo inflammatory ’reaction mediated by sensitized T cells that is evoked by
contact with the antigen with which the animal had been immunized.
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males) were reexposed to the CS on Days 13, 16, and 19 of gestation, there
was a depression of humoral and cell-mediated immunity in their un-
manipulated offspring.
Effects of Conditioning on Nonimmunologically Specific
In addition to studying antibody- and cell-mediated immunity, immunologists
also study the nonimmunologically specific in vitro actions of natural killer
cells and mitogens. These are among the most frequently used measures in
behavioral experiments. Natural killer (NK) cells are large granular lympho-
cytes that nonspecifically attack and destroy certain virus-infected cells and
tumor cells and may be involved in preventing tumor metastasis.
T and/or B lymphocytes can be induced to proliferate in vitro by stimula-
tion with various lectins (chemical substances obtained from plants), and the
lymphoproliferative response to such mitogens has been used to indicate an
alteration of the physiological state of T or B cells in a particular lymphoid
compartment (e.g. spleen, lymph nodes, peripheral blood). Changes in mitt-
genie responsiveness, however, do not necessarily reflect an organism’s abil-
ity to respond to antigens in vivo or in an immunologically specific manner.
In a comprehensive series of experiments, Lysle and his colleagues (1988,
1990a,b, 1991, 1992b) characterized the conditioned suppression of a variety
of nonspecific responses in rats rcexposcd to cues previously paired with
stressful stimulation. Compared to nonconditioned animals, to conditioned
animals exposed to novel environmental cues, and to animals exposed to cues
explicitly unpaired with the UCS, animals reexposed to auditory (or visual)
cues paired with electric shock stimulation showed a reliable suppression of
lymphoproliferative responses to concanavalin A (Con A) and phytohemag-
glutinin (PHA) (two T cell mitogens), lipopolysaccharide (LPS) (a
mitogen), interleukin-2 (IL-2)
production, and NK cell activity. As expected,
exposure to the CS before conditioning retarded development of the condi-
tioned response, and unreinforced exposures to the CS resulted in experimen-
tal extinction (Lysle et al 1988). In addition, the conditioned responses varied
as a function of both the timing of reexposure to the CS in relation to the time
of conditioning and the immune compartment from which the cells were
obtained (Lysle et al 1990a,b; Lysle & Maslonek 1991). In splenic lympho-
cytes there was a depressed response to T and B cell mitogens; in whole blood,
there was a suppression of the response to Con A and PHA, but not to LPS;
Macrophages and activated lymphocytes produce soluble products (cytokines), such as interleu-
kin-1 (IL-1), IL-2, interferons, and tumor necrosis factor that are involved in the proliferation,
differentiation, and effector functions of lymphocytes. In addition, they serve as "im-
munotransmitters" in the sense that some, if not all of them have effects within the central nervous
system and stimulate the release of hormones.
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cells obtained from mesenteric lymph nodes showed no effects of CS reexpos-
Using either a taste or odor aversion conditioning paradigm or a stressor as
the UCS, other studies have also observed the conditioned suppression of
lymphoproliferative responses both to mitogenic stimulation. (Drugan et al
1986; Kusnecov et al 1988; Neveu et al 1986, 1987), NK cell activity
(Gorczynski et al 1984; Hiramoto et al 1987; Lysle & Maslonek 1991;
O’Reilly & Exon 1986), and total white blood cell count (Klosterhalfen
Klosterhalfen 1987). The conditioned enhancement of NK cell activity has
also been reported (Hiramoto et al 1987; Solvason et al 1988, 1991). However,
some of these latter studies suffer from major design flaws, and others have
been unable to repeat these observations (Ader & Cohen 1991):
In a recent study, Coussons et al (1992) paired exposure to a distinctive
environmental setting with injections of morphine (which unconditionally
suppresses several nonspecific immune responses). Reexposure to the envi-
ronmental cues resulted in a conditioned suppression of splenic and peripheral
blood lymphocyte response to T and B cell mitogens, splenic NK cell activity,
and IL-2 production. These results are of additional interest in relation to the
issue of compensatory conditioning discussed above. The conditioned re-
sponse mimicked the unconditioned response rather than inducing an opposite
or compensatory response; induction of such a compensatory response, how-
ever, characterizes some of the other behavioral and physiological effects of
morphine (e.g. Siegel 1976, 1983).
As is the case with antibody-mediated responses, the above studies uncov-
ered no consistent relationship between conditioned behavioral responses and
conditioned changes in nonspecific defense reactions (Klosterhalfen
Klosterhalfen 1987; Kusnecov et al 1988; Neveu et al 1986, 1987; Solvason et
al 1988).
Antigen as Unconditioned Stimulus
In behavioral terms, an antigen is an unconditioned stimulus for activation of
the immune system and has been used as the UCS in a few studies. A condi-
tioned release of histamine, a nonspecific mediator of an allergic reaction,
occurred in response to a CS associated with the injection of the antigen,
bovine serum albumin (Dark et al 1987; Peeke et al 1987; Russell et al 1984),
and an increase in mast cell protease lI was observed in sensitized rats
reexposed to environmental cues previously paired with exposure to egg albu-
min (MacQueen et al 1989). With respect to an immune response, per se,
Gorczynski and his colleagues (Gorczynski et al 1982) repeatedly grafted
mice with allogeneic skin under a constant set of environmental conditions.
When these mice were given sham transplantations, there was an increase in
the number of precursor cytotoxic T lymphocytes. Subsequent unreinforced
exposures to the graft procedures resulted in extinction of the conditioned
response. These experiments are among the relatively few that have addressed
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conditioned immune responses as distinct from conditioned im-
munopharmacologic effects.
Biologic Impact of Conditioned Changes in Immunity
Although highly reproducible, the effects of conditioning in modulating im-
mune responses have been "relatively" small, and a recurring question has
been whether behaviorally induced alterations in immunocompetence have
any biological or clinical significance. So far, only a few studies have ad-
dressed this issue. In a study using mice that develop a systemic lupus-erythe-
matosus-like autoimmune disease (Ader & Cohen 1982), conditioned stimuli
were substituted for half of the weekly treatments with active im-
munosuppressive drug (CY). The onset of autoimmune disease in the geneti-
cally susceptible (NZB × NZW)F1 mice was thereby delayed using a cumula-
tive dose of CY that was not, by itself, sufficient to alter the progression of the
lupus-like disease. Also, in lupus-prone mice that had previously been given
weekly treatments with CY (paired with the taste of saccharin), reexposure
the CS after discontinuation of active drug treatment prolonged survival rela-
tive to conditioned mice that received neither active drug nor reexposure to the
CS (Ader 1985). Analogous results were obtained in studies of adjuvant-in-
duced arthritis in rats using either CY or cyclosporin as the UCS
(Klosterhalfen & Klosterhalfen 1983, 1990) and electric shock as the UCS
(Lysle et al 1992a), and in a study in which reexposure to a CS previously
paired with CY accelerated mortality among conditioned animals inoculated
with a syngeneic plasmacytoma (Gorczynski et al 1985).
Recently the therapeutic potential of conditioning was examined in differ-
ent transplantation models in an effort to prolong graft survival. A/J recipient
mice typically reject allogeneic skin grafts from BALI3/c or C57BL/6 donors
within two weeks. A low-dose injection of CY on the day of grafting, how-
ever, prolongs graft survival. In mice conditioned by the pairing of saccharin
and CY, reexposure to the CS alone on the day of grafting and at 5-day
intervals thereafter also prolonged survival of the skin allograft (Gorczynski
1990). In another recent study (Grochowicz et al 1991), reexposure of trans-
plant recipient rats to a CS previously paired with cyclosporin A extended the
survival of a heterotopic heart transplant. Experiments such as these hint at the
potential clinical significance of conditioned alterations in immune function.
Conditioning in Human Subjects
"As early as 1557, Amatus Lusitanus related the case of a Dominican monk,
who, whenever he perceived the odor of roses or saw them at a distance, was
immediately seized with syncope and fell unconscious to the ground" (Mac-
kenzie 1896:51, italics added). Mackenzie described his ability to provoke
asthmatic symptoms by presenting an artificial rose to an allergic patient,
which "forcibly illustrates the role of purely psychical impressions in awaken-
ing the paroxysms of the disease familiarly known as ’rose cold’" (Mackenzie
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1896:45). The literature contains descriptions of several similar cases of what
may represent conditioning phenomena (Hill 1930; Smith & Salinger 1933;
Dekker et al 1957). Laboratory studies in humans (Dekker et al 1957; Khan
1977) and animals (e.g. Ottenberg et al 1958) confirm the clinical suggestions
that exposure to symbolic, nonallergenic stimuli (CSs) previously associated
with allergens are capable of inducing asthmatic symptoms in some subjects.
More recent data provide preliminary evidence that conditioning may be
able to modify immune responses in human subjects. In a study by Ikemi &
Nakagawa (1962), four subjects received cutaneous stimulation with a methy-
lene blue solution (the CS) containing the extract of a Japanese lacquer tree
that unconditionally induced eczema within 24 hr. After an unspecified num-
ber of CS-UCS pairings, the CS alone elicited a skin reaction in all four
subjects. Smith & McDaniels (1983) also tried to condition a DTH response
human subjects. Healthy volunteers underwent tuberculin skin testing six
times at monthly intervals. In a counterbalanced manner, the "blinded" re-
search nurse administered tuberculin obtained from a green vial to one arm
and saline drawn from a red vial to the other arm. On the test trial, the contents
of the colored vials were switched; neither the experimenter nor the subject
was aware that tuberculin had now been put into the red vial, saline into the
green. Saline administered to the ann that had prcviously been treated with
tuberculin did not evoke a skin reaction, but there was a significant diminution
of the erythema and induration elicited by tuberculin in the arm previously
injected with saline. This finding is remarkably similar to that reported by
Moynihan et al (1989) in mice.
The failure of saline to evoke a skin reaction could be instructive, particu-
larly for the strategy underlying such research. First of all, the immunologic
mechanisms that could dampen an immunologically specific response are not
necessarily the same as those that might elicit or enhance that same response.
In the case of immunoenhancement, an immunogenic stimulus may be re-
quired, even if it alone is not sufficient to elicit a discernible reaction. A more
reasonable paradigm for the behavioral modification of an immune response,
then, may require the application of a minimally effective immunogenic stim-
ulus-one barely able to elicit a measurable response but sufficient to initiate
some early event in the immunologic cascade that leads to a typical immune
reaction. If "subthreshold" stimulation is capable of being potentiated by an
alteration of the neural and/or endocrine environment in which immune re-
sponses occur, one might be more likely to observe a behaviorally induced
alteration in immunologic reactivity under immunogenic stimulus conditions
that actually approximate natural conditions. Thus, in the present example, a
sensory stimulus (e.g. saline) that does not affect the immune system directly
may not suffice to elicit a tuberculin-induced skin reaction. But the superimpo-
sition of an immunologically neutral stimulus previously paired with activa-
tion of the immune system or the response induced by what would ordinarily
be a subthreshold immunogenic stimulus may be sufficient to elicit a discern-
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ible immune response. This basic strategy was used by Bovbjerg et al (1982,
1984) who demonstrated that the combination of a CS for immunosuppression
and a low dose of CY depressed a GvH response to a significantly greater
degree than the low dose of CY was able to accomplish alone.
The anticipatory nausea that occurs in 25-75% of patients undergoing
repeated chemotherapy for cancer appears to reflect a classically conditioned
response (Andrykowski et al 1985, 1988; Andrykowski & Redd 1987; Carey
& Burish 1988; Morrow & Dobkin 1988; Redd & Andrykowski 1982).
Bovbjerg et al (1990) studied women who had experienced at least three
sessions of chemotherapy to determine if cancer patients who displayed antic-
ipatory nausea and vomiting during the course of chemotherapy would also
show anticipatory immunosuppressive changes. Peripheral blood was obtained
at the patients’ homes 3-8 days before a scheduled chemotherapy session and
again in the hospital just before the intravenous drug infnsion. No differences
in NK cell activity or in cell counts or cell subset numbers were observed, but
in vitro proliferation in response to the T-cell mitogens PHA and Con A were
significantly lower prior to chemotherapy than the responses measured in the
home environment. There was no evidence that the decreased mitogen re-
sponses were related to anticipatory nausea or to the increased anxiety that
occurred in the hospital. This observation of anticipatory immunosuppression
is entirely consistent with the proposition that chemotherapy patients who
receive an immunosuppressive drug under a relatively constant set of environ-
mental conditions would show conditioned changes in immune function as
well as in behavior. The extent to which these behavioral and immune re-
sponses reflect the same underlying mechanisms--or, as the animal literature
suggests, represent independently conditioned responses--remains to be de-
termined and might prove important in the clinical management of chemother-
apy patients.
In the present context, "stress" refers to any natural or experimentally con-
trived circumstances that (intuitively, at least) pose an actual or perceived
threat to the psychobiological integrity of the individual. In nonhuman ani-
mals, environmental conditions that are apparently perceived as a threat to the
organism, and to which the organism cannot adapt, are accompanied by both
transient and relatively long-lasting psychophysiologic changes. We presume
that these changes contribute to the development of disease, especially if the
organism is at the same time exposed to potentially pathogenic stimuli. As
described below, however, the stress response is not uniformly detrimental to
the organism.
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Effects of Stress on Disease
Studies in humans have implicated psychosocial factors in the susceptibility to
and/or the progression of a variety of pathophysiologic processes including
bacterial, allergic, and autoimmune diseases that involve alterations in im-
munologic defense mechanisms. Specific examples include Epstein-Barr virus
infections, respiratory infections, streptococcal infections, asthma, and arthri-
tis. Comprehensive treatments of this subject have been provided recently by
S. Cohen & Williamson (1991) and Weiner (1977, 1991). Most of the experi-
mental work has been conducted with animals and indicates that a variety of
behavioral manipulations or stressors can influence susceptibility to a variety
of disease states in a variety of species. However, the stressors used do not all
produce the same effects. The impact and direction of the effects of stressful
stimulation depend upon the disease process to which the organism is concur-
rently subjected. For example, physical restraint in rodents increases suscepti-
bility to infection with herpes simplex virus (Bonneau et al 1991a,b; Rasmus-
sen et al 1957 ) and the Maloney sarcoma virus (Seifter et al 1973), has
effect on the response to an experimentally induced lymphorna (Greenberg et
al 1984), and decreases susceptibility to allergic encephalomyelitis (Levine
al 1962). Likewise, electric shock stimulation increases susceptibility to
Coxsackie B virus but decreases susceptibility to malaria (Friedman et al
1965) and to the spontaneous development of leukemia in AKR mice (Plaut
al 1981). Using the same disease outcome (e.g. encephalomyocarditis virus),
electric shock stimulation decreases susceptibility but the stimulation of han-
dling has no effect (Friedman et al 1969); and, while both electric shock and
handling decrease susceptibility to collagen-induced arthritis, a different
stressor, auditory stimulation, increases susceptibility (Rogers et al 1980a,b).
Analogous results are observed in studies on the development and progres-
sion of tumors in animals (Justice 1985; Sklar & Anisman 1981). Psychosocial
factors can influence the development and/or growth of tumors, but the direc-
tion of the effects depends on the tumor model chosen for study. The results
also depend on the quality, quantity, and duration of the stressor; the temporal
relationship between exposure to the stressor and the introduction of patho-
genic stimulation; socioenvironmental conditions (e.g. whether animals are
housed individually or in groups); and a variety of host factors (e.g. species,
strain, and sex). Further, the observed effects depend on the outcome measures
and sampling parameters selected for study. As described below, the effects of
stressful stimulation on immune function parallel those on stressful stimula-
tion and disease susceptibility. It seems evident--or, at least likely--that the
ability to predict the outcome of studies of the pathophysiologic effects of
stressful stimulation depends upon a more detailed understanding of the inter-
action between responses unconditionally elicited by specific kinds of poten-
tially pathogenic stimulation and the pattern of psychophysiological responses
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(including immunologic responses) induced by specific forms of stressful
While illustrations like those above document the effects of stressors on the
response to pathogenic agents, they do not provide evidence that these effects
are mediated by behaviorally induced alterations in immune function. Too
frequently, however, studies of the effects of stressors on tumor development
or metastasis are cited as evidence of the influence of stress or behavioral
interventions on immune function--even in the absence of any measure of
immune function. And even when simultaneous measures of immune function
are being measured, it is not always clear that the indexes chosen for study are
related to the. pathophysiologic process under study. It is not yet clear that
behaviorally induced perturbations in immune function can influence or medi-
ate the effects of psychosocial factors on the development or progression of
disease in humans, but provocative data are now being obtained (e.g. Glaser et
al 1987; Kemeny et al 1992), especially in relation to the experimental inocu-
lation of respiratory viruses .(Broadbent et al 1984; S. Cohen et al 1991;
Totman et al 1980).
More recent animal studies, however, are including biologically relevant
measures of immune function. Feng et al (1991), for example, infected mice
with influenza virus and observed a delay in the production of virus-specific
antibody levels in animals subjected to restraint. There were no detectable
differences in the magnitude of the humoral response ultimately attained,
however--a finding that could be related to an interaction between the tempo-
ral relationship of restraint and infection and the virulence of the pathogen
(Chao et al 1990). At a clinical level, psychosocial factors have been related
the manifestation of latent herpes virus infection (e.g. Glaser et al 1987).
Bonneau et al (1991a), studying the effects of a stressor on the murine re-
sponse to herpes simplex virus (HSV), found that repeated, prolonged periods
of physical restraint (16 hr/day for a varying number of days around the time
of inoculation) suppressed NK cell activity and the primary development of
HSV-specific cytotoxic T lymphocytes. Also, higher titers of infectious HSV
at the site of infection were recovered from restrained than from unrestrained
mice. Similar results were obtained by Kusnecov et al (1992) using overnight
exposure to intermittent electric shock stimulation (1 shock every 30 rain, on
average) on the day preceding and for eight days following virus infection. In
another study (Bonneau et al 1991b), restraint inhibited the in vitro activation
and/or migration of HSV-specific cytotoxic T lymphocytes from previously
primed mice--i.e, activation of HSV-specific memory cells was inhibited by
the physiological changes induced by the stressor. Other examples relate to
neoplastic disease (Ben-Eliyahu et al 1991; Brenner et al 1990). Using a tumor
model in which lung metastasis is thought to be controlled by NK cells,
Ben-Eliyahu and his colleagues (1991) found that, depending upon when the
stressor was imposed in relation to the effect of NK cells on the metastatic
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process, forced swimming decreased NK cell activity and resulted in a two-
fold increase in lung metastases.
Effects of Stress on Humoral and Cell-Mediated Immunity
Unlike the measurement of hormone levels or nonspecific defense reactions
that can be gauged by sampling factors circulating in blood, urine, saliva, etc,
the assessment of immune responses, such as most of those described above in
the context of disease susceptibility, requires that experimental subjects be
immunized. This additional variable adds layers of complexity to the charac-
terization of the effects of behavioral and other interventions on immune
function and the mediation of these effects. In addition to the quality and
quantity of environmental stimulation and the temporal relationship between a
stressor and immunization, one must, for example, consider the nature as well
as the concentration of antigen and the "cascade" of immune events that
eventuate in the production of antibody or a cell-mediated inflammatory re-
sponse. This complexity is reflected in much of the data describing the effects
of stressful stimulation on different aspects of immune function.
The relevance of the concentration of antigen used for immunization in
studies of stress has been noted in the past (Solomon et al 1974). In our view,
studies that address immune function per se use what might be described as
suprathreshold levels of antigenic stimulation---concentrations of antigen cal-
culated to induce a "robust" primary and secondary response. To the extent
that behaviorally induced neuroendocrine changes are capable of modulating
immune responses, the use of high levels of antigenic stimulation are not
comparable to the levels of antigen exposure experienced by the organism
under natural conditions and could be counterproductive as a research strategy
designed to elaborate behaviorally induced alterations in immunocompetence.
For these reasons, Moynihan et al (1990a) studied the effects of a stressor
(electric shock) on the response to low-dose antigenic stimulation. An im-
munizing dose of as little as 1 btg of the protein antigen keyhole limpet
hemacyanin (KLH) was insufficient to elicit a detectable primary response but
was sufficient to prime mice. When shock was administered for seven days
before and after immunization or only on one day, 24 hr after priming, mice
exposed to the stressor showed a depressed antibody response to challenge
with a second injection of 1 ~tg of KLH relative to control mice that were
simply placed into the shock apparatus or that remained unmanipulated. When
mice were challenged with a higher dose of KLH (5 lag) there were no group
differences. It is thus possible that concentrations of antigen that uncondition-
ally elicit robust immune responses could mask the effects of behavioral
For the most part, antibody production is suppressed by stressful stimula-
tion. Although differential housing (frequently mislabeled as "crowding" or
"isolation") may not qualify as a stressor, the manner in which animals are
housed or a change in housing conditions is sufficient to influence primary
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and/or secondary antibody responses to several different antigens (e.g.
Cunnick et al 1991; Edwards & Dean 1977; Edwards et al 1980; Glenn &
Becker 1969; Rabin et al 1987a,b; Rabin & Salvin 1987; Solomon 1969;
Vessey 1964). Antibody responses are also suppressed when submissive, in-
truder, and attacked and defeated rats are subsequently immunized (13eden
Brain 1982, 1984; Fauman 1987; Fleshner et al 1989; Ito et al 1983). A recent
review of these data has been provided by Bohus & Koolhaas (1991). Even the
odors emitted by mice subjected to stressful stimulation are sufficient to influ-
ence antibody production in consPeeific recipients. In one study (Zalcman et
al 1991 a,b), the antibody response to SRBC was suppressed in mice placed
into an apparatus vacated by conspecifics that had been exposed to a presumed
stressor; in another study (Cocke et al 1992), immunization with KLH follow-
ing prolonged exposure to alarm signals emitted by conspecifics undergoing
concurrent stimulation enhanced antibody responses in the group-housed re-
Antibody responses are influenced by early separation experiences. In rats,
brief handling and separation from the mother increased both primary and
secondary antibody responses to flagellin, a bacterial antigen (Solomon et al
1968), In mice, early separations from the mother resulted in a decreased
anti-SRBC antibody response (Michaut et al 1981), and separation from the
mother and rearing environment influenced the antibody response of monkeys
to an antigenic challenge (e.g. Coe et al 1985, 1988).
Okimura and his colleagues (Okimura & Nigo 1986; Okimura et al
1986b,c) found that serum antibody titers and the number of antibody-forming
splenic cells of mice were depressed if physical restraint (12 hr/day on two
consecutive days) was imposed after, but not before, immunization with
SRBC, a T-cell dependent antigen. 13oth adrenalectomy and chemical sympa-
thectomy blocked the stressor-induced immunosuppression. The response to a
hapten (TNP) conjugated to a type 2 T cell-independent carrier (Ficoll)
not influenced by restraint, but there was enhanced antibody production in
response to a type 1 T cell-independent antigen (LPS). In this case, adrenalec-
tomy, but not sympathectomy, blocked the enhanced response. The differen-
tial sensitivity of type 1 and type 2 T cell-independent antigens, which activate
different populations of 13 cells, is of additional interest in relation to thc
differential effects of conditioning on the response to these antigenic stimuli
(see N. Cohen et al 1979; Schulze et al 1988; Wayner et al 1978).
Both primary and secondary antibody responses are suppressed when rats
are subjected to inescapable electric shock stimulation daily beginning before
and continuing after immunization with KLH (Laudenslager et al 1988). Ro-
tating mice after but not before immunization with SRBC also depressed the
immune response to SRBC (Esterling & Rabin 1987). In contrast, avoidance
conditioning depressed the antibody response to SRBC relative to yoked ani-
mals that experienced unavoidable shock and an apparatus control group
(Mormede et al 1988). The degree to which rats could avoid or escape shock
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influenced the immune response, but not in the hypothesized direction. Zalc-
man and his colleagues (1988) subjected mice to a single session of footshock
0, 24, 48, 72, or 95 hr after immunization with SRBC. Both the number of
antibody-forming cells and serum anti-SRBC antibody titers were depressed,
but only in mice subjected to the stressor 72 hr after immunization, suggesting
that there is a critical period for this acute stressor, at least, on antibody
production. Based on changes in norepinephrine activity within the central
nervous system that result from this same schedule of electric shock treatment
(Anisman et al 1987; Zacharko & Anisman 1988), Zakman et al expected that
"controllability" would have influenced the immune response. There were,
however, no differences between mice that were and were not able to escape
the electric shock.
A seemingly innocuous form of stimulation with the immediate and long-
teim ability to influence antibody production is the handling of animals. Moy-
nihan et al (1990b) found that antibody production in response to KLH was
attenuated in adult mice that were immunized after a 2-week period of daily
handling. Raymond et al (1986) found that, depending on strain, rats that were
simply handled during the neonatal period had suppressed antibody titers in
response to subsequent immunization with SRBC. In response to flagellin
administration, adult rats handled during infancy showed an enhanced anti-
body response. In related research, Taylor & Ross (1989) found that neonatal
restraint (1 hr/day during the first 10 days of life) suppressed antibody re-
sponses to immunization with pneumococcal polysaccharide in adult rats. In
adult animals, the same restraint imposed for 3 weeks followed by a 3-week
interval before immunization had no discernible effects.
Moynihan and her
associates (Moynihan et al 1989) subjected mice to a different number
intraperitoneal (ip) injections of saline or just handling during the 2-week
period before the animals were injected with antigen. Daily handling as well
as the repeated ip injections of saline attenuated the production of antibody in
response to KLH relative to a group of unmanipulated mice. Whether there
was an attenuated response in the manipulated animals or an exaggerated
response in thc unmanipulated animals cannot be determined. Whether the
difference is a reflection of conditioning processes also remains to be deter-
mined. In either case, methodological questions arise about the control or
"resting" state of immunized animals.
With respect to cell-mediated immune responses, animals subjected to
stressors tend to show delayed skin graft rejection (Wistar & Hildemann 1960)
and suppressed DTH responses (Okimura et al 1986a). In a series of experi-
ments by Blecha and his colleagues (1982a,b), restraint, heat, and cold, three
commonly used stressors, had different effects on two different cell-mediated
The limited data available suggest that an exploration of the long-term effects of early life
experiences on immune flmction would be a fruitful avenue of research (Ader 1983; O’Grady
Hall 1991).
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immune responses. Restraint imposed before sensitization or challenge sup-
pressed the delayed cutaneous hypersensitivity response to SRBC. Exposure
to cold for two days after sensitization also depressed the DTH response,
whereas exposure to cold for eight days increased the DTH response. Heat
exposure invariably increased the hypersensitivity response. Contact hyper-
sensitivity to dinitrofluorobenzene was increased by each of these stressors.
Further, adrenalectomy or treatment with metapyrone abrogated the stressor-
induced suppression of DTH but had no effect on the strcssor-induced en-
hancement of the contact sensitivity response. Again, the literature provides
little justification for generalizing from one stressor to another---or from one
aspect of immune function to another.
Another immunologically relevant reaction to stressors is a suppression of
macrophage function (Pavlidis & Chirigos 1980; Jiang et al 1990; Okimura et
al 1986a; Qunidos et al 1986; Zwilling et al 1990), which may be mediated by
a stressor-induced depression of IFN production (Glascr et al 1986;
Sonnenfeld et al 1992). The expression of class II major histocompatibility
complex antigens by macrophages (glycoproteins that, together with pro-
cessed antigen, are presented to and recognized by lymphocytes) was de-
creased by physical restraint (Zwilling et al 1990) and cold water exposure
(Jiang et al 1990); in the study by Sonnenfeld et al (1992), electric shock
suppressed IFN-gamma production and the expression of class II antigens
which could, in turn, influence antibody- and cell-mediated immunocompet-
Effects of Stress on Nonimmunologically Specific Reactions
As in the case of antibody- and cell-mediated immunity, the effects of
stressors on nonspecific defense reactions are generally suppressive, but not
uniformly so (Croiset et al 1987; Lysle et al 1990a,b; Monjan & Collector
1977; Rinner et al 1992; Weiss et al 1989b).
The differential housing of rodents results in differences in
lymphoproliferative responses to mitogens, NK cell activity, and IL-2 produc-
tion (Ghoneum et al 1987; Jessop et al 1988; Rabin et al 1987a,b; Rabin
Salvin 1987), the direction and magnitude of the effects being determined by
species, strain, sex, and duration of housing. Other agonistic social interac-
tions can also reliably influence the response to T and B cell mitogens, NK
cell activity, and IL-2 production in fish as well as rodents (Bohus & Koolhaas
1991; Faisal et al 1989; Ghoneum et al 1988; Hardy et al 1990; Raab et al
1986). In addition to changes in antibody production, Cocke et al (1992) also
found reduced splenic NK cell cytotoxicity in mice exposed to the odors
emitted by footshocked conspecifics.
In general, the in vitro response of laboratory rodents to T cell mitogens in
splenic and/or peripheral blood lymphocytes decreases following relatively
acute exposure to a variety of stressors such as restraint, noise, and swimming
(Jiang et al 1990; Monjan & Collector 1977; Rinner et al 1992; Zha et al
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1992), and as a result of separation experiences (Ackerman et al 1988).
effects of separation experiences from mothers or peers in several nonhuman
primate species can have long-lasting effects (Coe et al 1989; Friedman et al
1991; Gust et al 1992; Laudenslager et al 1985, 1990). Increases and decreases
in lymphocyte proliferation have also been observed in handled animals, de-
pending on the amount of handling and the age at which it is experienced
(Lown & Dutka 1987; Moynihan et al 1990b; Rinner et al 1992). Similarly,
NK cell activity is frequently, but not invariably, depressed following acute
exposure to a variety of stressors (Aarstad et al 1983; Jiang et al 1990;
Moynihan et al 1990a; Okimura et al 1986a; Steplewski & Vogel 1986;
Steplewski et al 1985).
Electric shock stimulation has been the most frequently used stressor in
studies of nonspecifically stimulated defense reactions and thus provides the
more systematic data. Keller and his associates (1981) found that, with in-
creasing intensities of electric shock over a period of 18 hr, there was a
corresponding decrease in the proliferation of peripheral blood lymphocytes in
response to PHA, even when the assay was based on a constant number of
cells to correct for the stressor-induced decrease in the total number of circu-
lating lymphocytes. Less reliable effects were found in the response of splenic
lymphocytes, although Weiss et al (1989b), using the same paradigm, found
significant suppression of lymphoproliferation of both splcnic and blood lym-
phocytes. Under these conditions, they also found a decline in IL-2 and inter-
feron (IFN) production. Batuman et al (1990) obtained essentially the
results varying the number of days of electric shock stimulation and measuring
the response to both Con A and PHA. The proliferative response to B cell
mitogens (pokeweed mitogen and LPS) was not influenced by the stressful
stimulation. These investigators also noted a decrease in the total number of
splenic and peripheral blood lymphocytes, particularly of CD8+ cells. In addi-
tion, IL-2 production was diminished after as little as one day of exposure to
the 3-hr period of stimulation.
Lysle et al (1987) also found that a single session of approximately 1 hr
stressful stimulation during which rats received 8 or 16 (but not 4) signaled
footshocks was sufficient to depress the proliferative response of splenic and
peripheral blood lymphocytes to Con A stimulation. After five days of stimu-
lation, the response of spleen but not blood cells had recovered. Similar effects
were obtained by Cunnick et al (1988). Thus, whether one varies the intensity
of electric shock, the number of sessions of stimulation, or the number of
shocks per session, the magnitude of this form of stressful stimulation is
related to the magnitude of the changes in at least some measures of cellular
host defenses in some immune compartments. However, results obtained by
Livnat et al (1985) and Lysle et al (1990b) with electric shock and by Weiss
al (1989b) with qualitative and quantitative differences in stressful stimulation
suggest that this relationship may not be linear.
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The ability to predict or control the effects of stressful stimulation has
become a major focus of stress-related research and, as a result, the effects
obtained by Laudenslager et al (1983) indicating that inescapable but not
escapable footshock depressed mitogen responsiveness in rats has been cited
frequently. Less frequently cited, however, is the report by these investigators
(Maier & Laudenslager 1988) of their inability to reproduce these effects.
contrast to the effects on antibody production, however, Mormede and his
colleagues (1988) found that "control" did influence the response to mitogens.
Rats subjected to inescapable or unsignaled electric shock stimulation showed
a suppression of the lymphoproliferative response to T-cell mitogens. Also,
preliminary data obtained by Shavit et al (1983) indicated that inescapable but
not escapable shock suppressed splenic NK cell activity in rats. In another
preliminary study (Irwin & Custeau 1989), however, signaled electric shock
resulted in a more pronounced suppression of NK cell activity than unsignaled
Electric shock stimulation also suppresses NK cell activity (Cunnick et al
1988; Keller et al 1988; Lysle et al 1990a; Lysle & Maslonek 1991; Shavit et
al 1984; Weiss et al 1989b), the kinetics of which are strain dependent in mice
(Zalcman et al 1991a). Shavit and his colleagues (1984, 1986) found
intermittent electric shock stimulation, which induces an opioid-mediated an-
algesia, also depresses NK cytotoxicity, whereas continuous shock, which
results in a nonopioid analgesia, has no such effect.
There are no definitive data on the mediation of behaviorally conditioned or
stressor-induced changes in either specific or nonspecific defense system re-
sponses. It is clear that different immunologic and neuroendocrine mecha-
nisms are involved in mediating the effects of different behavioral interven-
tions on different immune responses measured in different compartments of
the immune system.
The available data suggest that the effects of conditioning could be medi-
ated by a preferential effect on T cells. Conditioned suppression of
lymphoproliferative responses in rats and mice, for example, has been ob-
served in response to T-cell mitogens but not (or less reliably) in response
B-cell mitogens (Kusnecov et al 1988; Lysle et al 1990b, 1991; Neveu et al
1986). Adoptive transfer experiments also suggest that conditioning may be
mediated by T cell changes (Gorczynski 1987). Splenocytes from conditioned
or experimentally naive animals were transferred into (irradiated) naive
conditioned animals that were or were not subsequently reexposed to the CS.
Studies of stressor control in human subjects (Sieber et al 1991; Weisse et al 1990) yield
imilar contrasting effects.
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The observed increases or decreases in the antibody-forming cell response to
SRBC depended on the donor cells and the conditioning treatment experi-
enced by the recipient. The separate transfer of enriched T and B cells into
naive or conditioned mice suggested that conditioning effects were attribut-
able to the adoptively transferred T cells (Gorczynski 1991). The question
whether conditioning can modulate the antibody response to different types of
T-cell independent antigens has not been resolved (N. Cohen et al 1979;
Schulze et al 1988; Wayner et al 1978).
Stressful stimulation also seems to have greater effects on T cell than on B
cell function (e.g. Batuman et al 1990; Lysle et al 1990b; Mormede et al 1988;
Moynihan et al 1990b). Several investigators have demonstrated conditioned
and stressor-induced decreases in IL-2 production that might account for the
suppression of T cell proliferation (e.g. Batuman et al 1990; Ghoneum et al
1988; Hardy et al 1990; Kandil & Borysenko 1988; Weiss et al 1989b).
However, adding IL-2 to incubated lymphocytes did not normalize the
stressor-induced suppression of lymphoproliferation (Weiss et al 1989a).
These investigators did find that electric shock decreased the expression of
IL-2 receptors on lymphocytes, suggesting that a compromised ability to re-
spond to IL-2 may contribute to stressor-induced immunosuppression (and,
via neural and/or endocrine pathways, conditioned antibody- and/or cell-medi-
ated immune responses, as well).
The in vitro T cell effects of behavioral interventions appear to be differen-
tially expressed by splenic and blood lymphocytes in the case of both condi-
tioning (Lysle et al 1990a; Lysle & Maslonek 1991) and stressful stimulation
(Cunnick et al 1988; Keller et al 1983, 1988; Lysle et al 1987; Rinner et al
1992). This could reflect the trafficking of lymphocytes and a resulting differ-
ence in the kinetics of the response in these two compartments (Cunnick et al
1988; Lysle et al 1987); it could also relate to differences in the manner in
which splenic and peripheral blood lymphocytes were cultured. However, the
fact that there is noradrenergic innervation of the spleen (Felten et al 1987)
and that the stressor-induced suppression of splenic but not blood lymphocyte
proliferation is blocked by [~-adrenergic antagonists (Cunnick et al 1990)
suggests the operation of different mediating mechanisms.
With respect to neuroendocrine influences, it is reasonable to hypothesize
that conditioned alterations of immunologic reactivity could be mediated by
conditioned ncuroendocrine changes, but data collected thus far are inconsis-
tent with the proposition that such effects are mediated simply by nonspecific,
stressor-induced changes in hormone levels. As reviewed elsewhere (Ader
Cohen 1991), an extensive literature and other recent studies (e.g. Roudebush
& Bryant 1991) directly contradict or are inconsistent with predictions that
would follow from a "stress mediation" hypothesis of the effects of condition-
ing or that conditioning effects are adrenal dependent. An elevation in
glucocorticoids is a common (and sometimes defining) characteristic of
stress response, and exogenously administered glucocorticoids are generally
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(but not uniformly) immunosuppressive (Munck & Guyre 1991). Nonetheless,
an endogenous elevation in adrenocortical steroids in response to different
stressors cannot be invoked to account for most of the stressor-induced
changes in immunocompetence.
In terms of antigen-specific immune responses, Okimura et al (1986b)
found that adrenalectomy blocked the suppression of antibody responses to
SRBC in rats that had been subjected to restraint, but adrenalectomy did not
influence the immunosuppressive effects of rotation (Esterling & Rabin 1987).
In studies using electric shock (Laudenslager et al 1988; Mormede et al 1988),
no relationship between corticosterone levels and suppressed antibody produc-
tion in rats was seen. Blecha et al (1982b) found that adrenalectomy attenuated
the suppression of a DTH response in restrained mice but did not affect the
restraint-induced enhancement of contact hypersensitivity. With respect to
nonspecific reactions, electric shock in rats induced a lymphopenia that was
adrenal dependent (Keller et al 1981); the stressor-induced suppression
mitogen responsiveness, however, was unaffected by adrenalectomy (Keller et
al 1983). The suppressed lymphoproliferative response of splenic T lympho-
cytes, in particular, has been shown consistently to be independent of stressor-
induced adrenal activity (e.g. Lysle et al 1990b; Monjan & Collector 1977;
Mormede et al 1988; Rabin et al 1987a, b; Weiss et al 1989b). The stressor-in-
duced suppression of NK cell activity and IL-2 production are not blocked by
adrenalectomy (e.g. Weiss et al 1989b).
Both conditioned and stressor-induced alterations of immune and nonspe-
cific defense responses have been attributed to the actions of catecholamines.
Gorczynski & Holmes (1989), for example, reported that both chlorpromazine
and amitriptyline abolished conditioned immunosuppressive responses based
on the pairing of a gustatory stimulus with CY. Lysle et al (1992a) reported
that the [3-adrenergic antagonist propranolol blocked the effects of conditioned
stressor effects on the development of adjuvant-induced arthritis; but propran-
olol itself may be capable of attenuating inflammatory responses (Kaplan et al
1980). Cunnick and her colleagues (1990) found that propranolo! and nadolol
(a ~-adrenergic antagonist that does not cross the blood-brain barrier) blocked
the electric shock-induced suppression of splenic but not peripheral blood
lymphocytes to Con A stimulation. Propranolol also blocked attenuation of the
lymphoproliferative response of splenic lymphocytes to a CS previously
paired with electric shock (Luecken & Lysle 1992). Neither propranolol nor
nadolol influenced the conditioned suppression of B cell mitogenesis of pe-
ripheral blood lymphocyte responses or IL-2 production, but both antagonists
attenuated the conditioned suppression of IFN-gamma. The peripherally act-
ing [~-adrenergic receptor antagonist also blocked the suppression of IFN-
gamma production induced by electric shock stimulation (Sonnenfeld et al
Using a different stressor (repeated exposure to cold), Carr et al (1992)
described an enhancement of splenic antigen-specific antibody production
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and, at the same time, suppressed or unaltered serum levels of im-
munoglobulins. In this instance, phentolamine blocked the effects of cold
exposure and propranolol potentiated the effects of the stressor. While little is
known of the immunologic effects of catecholamines in vivo, it is relevant to
note that Zalcman et al (1991 a) were unable to detect any meaningful relation-
ship between the depression of brain levels of norepinephrine and the suppres-
sion of NK cell activity induced by one hour of uncontrollable electric shock
stimulation. It is evident that any involvement of catecholamines in the media-
tion of stressor-induced alterations of immunity is determined by interactions
involving the nature of the immune response and the compartment in which it
is measured and the neurochemical concomitants of the adaptive responses
induced by the nature of the stressor.
Opioids acting within the central nervous system have also been implicated
in the mediation of conditioned and stressor (electric shock)-induced alter-
ations of nonspecific defense responses. Cunnick and her colleagues (1988)
found that naltrexone, an opioid receptor antagonist, blocked a shock-induced
suppression of splenic NK cell activity but did not obviate suppression of the
splenic lymphocyte response to T cell mitogens. Lysle et al (1992b) found that
naloxone (in doses higher than those used by Cunnick et al) blocked the
conditioned suppression of NK cell activity and the depressed response to both
T and B cell mitogens. Although the association between an olfactory CS and
poly I:C was unaffected, subsequent enhancement of NK cell activity in re-
sponse to reexposure to the CS also could be blocked by naltrexone (Solvason
et al 1989). N-methylnaltrexone, a quaternary form of naltrexone that does not
cross the blood-brain barrier, did not interfere with these conditioned re-
That the effects of stressful stimulation on NK cell activity may be medi-
ated by centrally acting opioids is suggested by the observations that the
immunosuppression induced by electric shock was prevented by pretreatment
with naltrexone but not by the peripheral actions of N-methylnaltrexone, and
that a dose-dependent suppression of NK cell activity could be induced by
morphine (Shavit et al 1984). However, Shavit et al (1986) found that NK
activity was suppressed to the same extent following 4, 14, or 30 daily ses-
sions of electric shock stimulation, whereas tolerance to the immunosuppress-
ive effects of morphine developed after 14 sessions. Also, a stressor-induced
suppression of NK cell activity was observed in both morphine-naive and
morphine-tolerant rats. Thus, the suppression of NK cell activity in response
to morphine and to stressful stimulation is not mediated by precisely the same
mechanisms. Of related interest is the report that serum obtained from mice or
rats subjected to physical restraint (Zha et al 1992) and electric shock (Weiss
et al 1989a) contained one or more factors that could suppress the
lymphoproliferative response of peripheral blood lymphocytes from un-
manipulated animals. Neither adrenalectomy nor naltrexone treatment altered
this effect (Zha et al 1992).
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It may also be relevant that some studies have uncovered different changes
in mitogenesis and/or NK cell activity in animals subjected to avoidable or
unavoidable, escapable or inescapable, or signaled or unsignaled electric
shock (Irwin & Custeau 1989; Mormede et al 1988; Shavit et al 1983), despite
the fact that each of these stressful situations would fit the criterion for an
opioid-mediated analgesia that might be expected to suppress NK cell activity.
Other studies (e.g. Cunnick et al 1988; Keller et al 1988; Odio et al 1987) have
noted a dissociation between the effects of the same stressor, electric shock
(albeit of different magnitudes, intensity, and duration), on NK cell and mito-
gen responses, both of which have been observed to be blocked by naltrexone
treatment in one study (Lysle et al 1992b). There is abundant evidence that
opioids, for which there are receptors on lymphocytes (Blalock 1988), can
influence immune functions. It is not likely, however, that centrally acting
opioids are the sole mediator of either conditioned or stressor-induced alter-
ations of immunocompetence.
The fact that some agonistic or antagonistic neurochemical or pharmaco-
logic intervention can block or mimic the immunologic effects of reexposure
to a CS or stressful stimulation does not, in itself, constitute an explanation of
the behaviorally induced effects. It suggests only that such a pathway is one
(of perhaps several) means by which such an effect could occur. Indeed, the
complexity of the multiple communication channels between the brain and the
immune system provides any number of other pathways through which behav-
iorally induced alterations in immunity could be mediated. It is beyond the
scope of this review, however, to detail these interactions (see Ader et al
199 la); nor, because of the paucity of behavioral data, should we speculate on
their role in the psychophysiologic regulation of immunity. These interactions
can, however, be summarized as follows.
Primary (thymus, bone marrow) and secondary (spleen, lymph nodes, gut-
associated lymphoid tissues) lymphoid organs are innervated by the sympa-
thetic nervous system (Felten & Felten 1991), and lymphoid cells bear
receptors for many neuroendocrine and neurotransmitter signals that have
demonstrable immunomodulating effects (Blalock 1992). Moreover, microg-
lia cells of the central nervous system can produce cytokines (e.g. Carr 1992;
Guillian et al 1986). Conversely, lymphocytes can produce neuroendocrine
factors such as proopiomelanocortin-derived peptides (Blalock 1988). Also,
cytokines produced by macrophages and activated lymphocytes are signal
molecules ("immunotransmitters") that can energize the hypothalamo-pitu-
itary-adrenal axis (e.g. Besedovsky & del Rey 1991). This network provides
the structural foundation for and (in combination, perhaps) the mediation
various kinds of relevant observation: that lesioning or electric stimulation of
areas within the hypothalamus results in alterations in immune function
(Felten et al 1991), and peak antibody production is associated with changes
the electrical activity within the hypothalamus (Besedovsky et al 1977); that
hypophysectomy and changes in circulating levels of hormones and neuro-
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transmitters can influence immune responses (e.g. Berczi & Nagy 1991; Ader
et al 1990), and that immunologic reactions alter circulating levels of hor-
mones and neurotransmitters (e.g. Besedovsky & dcl Rey 1991); and that
behavioral manipulations (e.g. Pavlovian conditioning, stressful stimulation)
can, as described above, ~nodulate antigen-specific and nonspecific immune
responses, that the physiological effects of products of an activated immune
system can be conditioned (Dyck et al 1990), and that immunologic dys-
regulations have behavioral consequences (Ader et al 199 lb).
We cannot yet specify the mechanisms underlying the functional relation-
ship between the nervous system and the immune system--mechanisms
illustrated by conditioned and stressor-induced modulations of different com-
ponents of immunological defenses. In fact, for the most part we cannot yet
specify the functional significance of the neuroanatomical, neurochemical,
and neuroendocrine connections between the brain and the immune system.
Only in recent years, however, has the autonomy of the immune system been
seriously questioned. Behavioral research has played a central and enabling
role in provoking studies of interactions between the central nervous system
and the immune system, and now represents only one of several lines of
research that provide converging support for an integrated approach to an
understanding of adaptive processes.
The acquisition and extinction of the conditioned suppression or enhancement
of one or another parameter of antigen-specific and nonspecific defense sys-
tem responses have been documented in different species under a variety of
experimental conditions. Similarly, stressful stimulation influences antigen-
specific as well as nonspecific reactions. Moreover, both conditioning and
stressful stimulation exert biologically meaningful effects in the sense that
they can alter the development and/or progression of what are presumed to be
immunologically mediated pathophysiologic processes. These are highly re-
producible phenomena that illustrate a functional relationship between the
brain and the immune system. However, the extent to which one can general-
ize from one stressor to another or from one parameter of immunologic reac-
tivity to another is limited. Few generalizations are possible because the direc-
tion and/or magnitude of the effects of conditioning and "stress
in modulating
immune responses clearly depend on the quality and quantity of the behavioral
interventions, the quality and quantity of antigenic stimulation, the temporal
relationship between behavioral and antigenic stimulation, the nature of the
immune response and the immune compartment in which it is measured, the
time of sampling, a variety of host factors (e.g. species, strain, age, sex), and
interactions among these several variables. It seems reasonable to assume that
the immunologic effects of behaviorally induced neural and endocrine re-
sponses depend on (interact with) the concurrent immunologic events upon
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which they are superimposed. Conversely, the efficacy of immunologic de-
fense mechanisms seems to depend on the neuroendocfine environment on
which they are superimposed. We seek to determine when and what im-
munologic (or neuroendocrine) responses could be affected by what neuroen-
docrine (or immunologic) circumstances. We therefore need studies that pro-
vide a parametric analysis of the stimulus conditions, the neuroendocrine
and/or immunologic state upon which they are superimposed, and the re-
sponses that are being sampled.
The neural or neuroendocrine pathways involved in the behavioral alter-
ation of immune responses are not yet known. Both conditioning and stressor-
induced effects have been hypothesized to result from the action of
adrenocortical steroids, opioids, and catecholamines, among others. Indeed, all
of these have been implicated in the mediation of some immunologic effects
observed under some experimental conditions. We assume that different con-
ditioning and stressful environmental circumstances induce different constel-
lations of neuroendocrine responses that constitute the milieu within which
ongoing immunologic reactions and the response to immunologic signals
occur. Based on the complexity of the network of connections and regulatory
feedback loops between the brain and the immune system, these processes
appear to involve both neural and endocrine signals to the immune system and
signals from the immune system that are received by the nervous system and
provoke further neural and endocrine adjustments. Considering the variety of
immunologic processes involved, it does not seem likely--or biologically
adaptive--that there would be any single mediator of the diverse effects of
either conditioning or stressful stimulation. It does not seem likely, however,
that the ultimate elaboration of the mechanisms underlying behaviorally in-
duced alterations of immune function will have important clinical and thera-
peutic implications.
Preparation of this review was supported by a USPHS Research Scientist
Award (K05 MH-06318) to R.A.
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... Repeated immobilization stress is an easy and well-known method to induce chronic physical and emotional stress [1]. The psychological and physiological changes to repeated immobilization stress are initiated by activation of the hypothalamic-pituitary adrenal axis, and these results in the release of catecholamines and stress hormones such as corticotropin-releasing factor (CRF) [2,3]. ...
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Grounding is a therapeutic technique that involves doing activities that “ground” or electrically reconnect us to the earth. The physiological effects of grounding have been reported from a variety of perspectives such as sleep or pain. However, its anti-stress efficacy is relatively unknown. The present study investigated the stress-related behavioral effects of earthing mat and its neurohormonal mechanisms in the Sprague–Dawley male rat. Rats were randomly divided into four groups: the naïve normal (Normal), the 21 days immobilization stressed (Control), the 21 days stressed + earthing mat for 7 days (A7) or 21 days (A21) group. The depressive-and anxiety like behaviors were measured by forced swimming test (FST), tail suspension test (TST) and elevated plus maze (EPM). Using immunohistochemistry, the expression of corticotrophin-releasing factor (CRF) and c-Fos immunoreactivity were analyzed in the brain. In the EPM, time spent in the open arm of the earthing mat groups was significantly increased compared to the Control group (p < 0.001), even though there were without effects among groups in the FST and TST. The expression of CRF immunoreactive neurons in the earthing mat group was markedly decreased compared to the Control group. Overall, the earthing mat reduced stress-induced behavioral changes and expression of c-Fos and CRF immunoreactivity in the brain. These results suggest that the earthing mat may have the potential to improve stress-related responses via the regulation of the corticotrophinergic system.
... Psychological stress occurs when an individual's resources are exhausted or exceeded by the environment and endangered the individual (Lazarus and Folkman, 1984). Physiological and psychological problems can result from chronic or long-term stress (Ader & Cohen, 1993). On the other hand, while chronic stress affects people's health, short-term stress has a benefit, since it's one of nature's fundamental survival mechanisms. ...
... • As we have discussed and reviewed previously (Rancourt, Baudin and Mercier, 2021a), chronic stress debilitates the immune system and is arguably the dominant determinant of individual health (Cohen, Tyrrell and Smith, 1991;Ader and Cohen, 1993;Cohen et al., 1997;Sapolsky, 2005;Cohen, Janicki-Deverts and Miller, 2007;Dhabhar, 2014;Prenderville et al., 2015). Furthermore, the molecular and physiological mechanisms for suppression of the immune system by experienced chronic stress are being elucidated more and more (Devi et al., 2021;Udit, Blake and Chiu, 2022). ...
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All-cause mortality by time is the most reliable data for detecting and epidemiologically characterizing events causing death, and for gauging the population-level impact of any surge or collapse in deaths from any cause. Such data is not susceptible to reporting bias or to any bias in attributing causes of death. We compare USA all-cause mortality by time (month, week), by age group and by state to number of vaccinated individuals by time (week), by injection sequence, by age group and by state, using consolidated data up to week-5 of 2022 (week ending on February 5, 2022), in order to detect temporal associations, which would imply beneficial or deleterious effects from the vaccination campaign. We also quantify total excess all-cause mortality (relative to historic trends) for the entire covid period (WHO 11 March 2020 announcement of a pandemic through week-5 of 2022, corresponding to a total of 100 weeks), for the covid period prior to the bulk of vaccine delivery (first 50 weeks of the defined 100-week covid period), and for the covid period when the bulk of vaccine delivery is accomplished (last 50 weeks of the defined 100-week covid period); by age group and by state. We find that the COVID-19 vaccination campaign did not reduce all-cause mortality during the covid period. No deaths, within the resolution of all-cause mortality, can be said to have been averted due to vaccination in the USA. The mass vaccination campaign was not justified in terms of reducing excess all-cause mortality. The large excess mortality of the covid period, far above the historic trend, was maintained throughout the entire covid period irrespective of the unprecedented vaccination campaign, and is very strongly correlated (r = +0.86) to poverty, by state; in fact, proportional to poverty. It is also correlated to several other socioeconomic and health factors, by state, but not correlated to population fractions (65+, 75+, 85+ years) of elderly state residents.
... Cardiovascular conditioning studies have reliably demonstrated that humans can voluntarily learn to increase or decrease heart rate and blood pressure [111,114,115,117]. Other studies with humans and animals have also observed anticipatory and voluntary control of visceral responses, including heart rate, blood pressure, blood volume, breathing, gastrointestinal function, bowel control, pupil dilation, electrodermal activity, body temperature, immunosuppression and blood oxygenation level [112,113,[120][121][122][123][124][125][126][127][128]. Overall, these psychophysiological studies suggest that learning of visceral responses, at least for those which humans can exert voluntary control, may follow similar principles of adaption observed in motor behaviour, such as stages of learning and change in behavioural control, effect of prior knowledge, transfer of learning or generalization, efficiency of feedback, effector specificity and awareness of the learned visceral response [113,114,117,[129][130][131]. ...
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In the brain, the insular cortex receives a vast amount of interoceptive information, ascending through deep brain structures, from multiple visceral organs. The unique hierarchical and modular architecture of the insula suggests specialization for processing interoceptive afferents. Yet, the biological significance of the insula's neuroanatomical architecture, in relation to deep brain structures, remains obscure. In this opinion piece, we propose the Insula Hierarchical Modular Adaptive Interoception Control (IMAC) model to suggest that insula modules (granular, dysgranular and agranular), forming parallel networks with the prefrontal cortex and striatum, are specialized to form higher order interoceptive representations. These interoceptive representations are recruited in a context-dependent manner to support habitual, model-based and exploratory control of visceral organs and physiological processes. We discuss how insula interoceptive representations may give rise to conscious feelings that best explain lower order deep brain interoceptive representations, and how the insula may serve to defend the body and mind against pathological depression.
The need for additional immunotoxicity testing should be decided on the basis of a weight of evidence assessment, taking into account all available information. Immunotoxicity is defined in the ICH S8 specifically guideline as unintended immunosuppression or enhancement. Unanticipated immunotoxicity is infrequently observed with drugs that have been approved for marketing. The immune system is divided into two defense mechanisms: nonspecific, or innate, and specific, or adaptive, mechanisms that recognize and respond to foreign substances. The immune system is a highly integrated and regulated network of cell types that requires continual renewal to achieve balance and immunocompetence. The various cells of the immune system may differ in their sensitivity to a given xenobiotic. The drug or metabolite can act as a hapten and covalently bind to a protein or other cellular constituent of the host to appear foreign and become antigenic.
Mens immunsystemet tidligere blev betragtet som en overvejende autonom kropslig forsvarsmekanisme, anerkendes det i dag som et system, der interagerer med og reguleres af centralnervesystemet. Under fællesbetegnelsen »psykoneuroimmunologi « har tværvidenskabelige undersøgelser påvist forekomsten af en række kommunikationsforbindelser mellem hjernen og immunsystemet, der muliggør interaktion mellem de to systemer. Sådanne forbindelser udgør grundlaget for udforskningen af såvel sammenhænge mellem psykologiske processer og immunsystemet som af den mulige betydning af psykosociale faktorer for udvikling af immunologiske og inflammatoriske lidelser.
Almost 2/3rds of stroke survivors exhibit vascular cognitive impairment and a third of stroke patients will develop dementia 1-3 years after stroke. These dire consequences underscore the need for effective stroke therapies. In addition to its damaging effects on the brain, stroke rapidly dysregulates the intestinal epithelium, resulting in elevated blood levels of inflammatory cytokines and toxic gut metabolites due to a ‘leaky’ gut. We tested whether repairing the gut via intestinal epithelial stem cell (IESC) transplants would also improve stroke recovery. Organoids containing IESCs derived from young rats transplanted into older rats after stroke were incorporated into the gut, restored stroke-induced gut dysmorphology and decreased gut permeability, and reduced circulating levels of endotoxin LPS and the inflammatory cytokine IL-17A. Remarkably, IESC transplants also improved stroke-induced acute (4d) sensory-motor disability and chronic (30d) cognitive-affective function. Moreover, IESCs from older animals displayed senescent features and were not therapeutic for stroke. These data underscore the gut as a critical therapeutic target for stroke and demonstrate the effectiveness of gut stem cell therapy.
Depression is recognized as a leading cause of disability worldwide although it lacks one of the typical characteristics of a disorder, disease or disability in the traditional sense, i.e., biological markers. Depression is difficult to characterize in that it is highly heterogeneous epidemiologically and symptomatically. Depression is often a comorbidity, associated with other physical or mental health disorders, and depressive symptoms occur on a spectrum of severity ranging from mild dysphoria to major depressive disorder (MDD). Comorbid depression is associated with an array of neurological disorders with neuroimmunological or neuroinflammatory mechanisms, as well as peripheral systemic inflammatory disorders such as rheumatoid arthritis, psoriasis, and cancers. Recent research on the immune mechanisms of depression has reproducibly demonstrated a robust association between biological markers of peripheral inflammation, e.g., blood levels of C-reactive protein, and depressive symptoms. However, there have been fewer brain imaging studies of inflammation-related depression, which are important for bridging the explanatory gap between peripheral immune states, like inflammation, and mental states, like depression, in humans. Chapter 1 introduces a dichotomy in thinking about depression, discussing briefly historical concepts that on one hand supported a monolithic view of the disorder, and on the other hand, alluded to greater complexity based on how the body might interact with the brain and mind. On this basis, I highlight areas of contemporary immunopsychiatric research that both support and challenge the hypothesis central to this thesis, that is, peripheral (bodily) inflammation may elicit depressive symptoms via brain functional abnormalities. In Chapter 2 I present a more focused discussion in the form of a literature review of current brain functional neuroimaging studies on inflammation-linked depression. I noted through this endeavor that the body of knowledge addressing fMRI abnormalities in inflammation-linked depression is presently limited, and it is further complicated by considerable variability in study setting, methodology, sample and analytic approaches. Peripheral inflammation has often been measured simply by blood concentration of C-reactive protein (CRP) and brain phenotypes have often been measured in a few, selected regions of interest (ROIs) rather than across the whole brain. Nonetheless, the extant literature very broadly converged to suggest the concept that dysregulation of the peripheral immune system could indeed be associated with brain functional abnormalities in depression. In Chapter 3, I describe the design and assessments used in an observational case-control study (BioDep) of three groups of participants, i.e., healthy controls (HC), low-CRP depression cases (CRP ≤ 3 mg/L), and high-CRP depression cases (CRP > 3 mg/L). All participants completed assessments of peripheral blood immune markers, behavioral questionnaires, resting-state fMRI, and a probabilistic reinforcement-learning task-based fMRI paradigm. On this basis, I tested the following key hypotheses which were the focus of subsequent chapters: (i) increased concentrations of innate and adaptive immune markers is characteristic of inflammation-linked depression, (ii) inflammation-linked depression is associated with diffuse functional connectivity abnormalities, (iii) increased peripheral inflammation attenuates functional connectivity in depression, and (iv) peripheral inflammation reorients response to affective experience in depression. In Chapter 4, I first investigated sociodemographic, clinical, behavioral and immune variability in the analyzable cohort (N = 129; Ndepression = 83). BMI and sex differed significantly between the low CRP (N = 50) and high CRP depression cases (N = 33), with both BMI and proportion of females being greater in the high CRP depression cases. Sex and BMI were therefore noted as potentially confounding variables that would require careful consideration in subsequent analyses. With regards to immune markers, I first performed a simple pair-wise correlational analysis on CRP and 16 other inflammatory proteins, i.e., cytokines and chemokines. Weighted network visualization, coupled with a literature search-based functional assignment of each biomarker, indicated that functionally-related inflammatory proteins were more strongly positively correlated with each other. Thus, concentrations of these clusters of immune markers were similarly increased or decreased in the blood. Next, I reduced the dimensionality of this multivariate biomarker dataset using principal component analysis (PCA) on 15 inflammatory proteins (excluding IL-6). This resulted in 5 selected principal components. I interpreted the first principal component (PC1) to be a weighted average of all inflammatory proteins or a global index of immune state. PC1 score was also positively correlated with neutrophil count. Chapter 5 marks the start of my investigation of the links between peripheral inflammation and the brain, using whole-brain functional connectivity (FC) measures derived from resting-state functional magnetic resonance imaging (fMRI) data. I conducted a two-fold exploratory analysis: (i) multi-granular decomposition of the functional connectome at coarse- and fine- grained anatomical resolutions, and (ii) a data-driven subnetwork-level decomposition of the functional connectome using network-based statistics (NBS). This non-parametric method of significance testing for high CRP depression case-control differences yielded a set of interconnected brain regions - in other words, a network - that showed progressively increased abnormalities, denoted by weaker and more negative functional connections, in high CRP depression cases, followed by low CRP cases, compared to controls. The attenuated functional connections were mainly anatomically located between the left insula/frontal operculum and posterior cingulate cortices. Meta-analytic search of an independent fMRI database suggested that this network was functionally specialised for interoception, i.e., brain sensing of internal bodily states for emotion modulation. In Chapter 6, the putative interoceptive network discovered by the case-control analysis of high CRP depression cases versus controls in Chapter 5 was used as a 'mask' to test the continuous association between brain functional connectivity and peripheral inflammation in all depression cases (including low CRP cases but excluding controls). There was robust negative scaling between average network connectivity (or 'within-network' connectivity) and CRP (N = 83), IL-6 (N = 72), and PC1 scores (N = 72) from the principal component analysis of 15 cytokines and chemokines in Chapter 4. Corroborating this association between functional connectivity and inflammatory proteins, neutrophil count (N = 36) also showed significant negative scaling with average network connectivity. These results are interpreted as evidence suggesting that inflammation-linked depression could be underpinned by abnormalities of interoceptive processing of afferent peripheral immune signals, and/or signaling in other motivational or reward-related circuits, which could be clinically manifest as dysregulation or misrepresentation of emotional states, i.e., feelings of depression. In Chapter 7, I investigated abnormalities of affective traits, e.g., anhedonia and pessimism, using task-based fMRI in inflammation-linked depression. Through a probabilistic reinforcement learning paradigm, I tested for evidence of hyposensitivity to reward, and hypersensitivity to punishment, with increasing inflammation. Voxel-wise activation was observed in key brain regions sensitive to monetary reward (ventromedial prefrontal cortex, vmPFC; nucleus accumbens, NAc) and punishment (insula) outcomes in all three groups (HC, low CRP depression and high CRP depression). However, there was no significant difference in activation between any two groups. Within depression cases, increasing CRP scaled negatively with activation in the right vmPFC and left NAc. However, there was no significant association between regional activation and severity of anhedonic or negative attitudes measured by Beck’s Depression Inventory (version II). Finally, in Chapter 8, I conclude by reviewing the initially proposed central hypothesis, noting that whilst the novel evidence generated by these studies provide some support for the hypothesis that peripheral inflammation is associated with functional abnormalities in depression-related brain networks, these data also prompt further refinement and evolution of this model. In particular, these results indicate that the brain circuits most sensitive to inflammatory states in depression may be functionally specialised for interoceptive sensing and processing of peripheral immune signals. These results have also shown that immune dysregulation in inflammation-linked depression is at the level of the 'immune interactome' - as opposed to a single immune marker in the periphery - warranting particular look into chemokines and immune cells, beyond CRP and IL-6. In view of these findings, I finally highlight the need for future work focused on interoceptive representation of peripheral immune signals within the brain, and CNS vascular physiology, that can together better delineate mechanisms of interaction between the brain and the body as demonstrated here in inflammation-related depression.
Background : Adaptogens are generally referred to the substances, mostly found in plants, which non-specifically increase resilience and chances of survival by activation of signaling pathways in affected cells. Purpose : This literature review was conducted to summarize the investigation, until March 2021, on selected adaptogenic plants and plant-derived substances. Study Design : Electronic databases were searched (up to March 2021) for in vitro and animal studies, as well as clinical trials. Moreover, all modes of action connected with the adaptogenic effects of plants and phytochemicals were collected. Methods : The search of relevant studies was performed within electronic databases including Scopus, Science Direct, PubMed, and Cochrane library. The most important keywords were adaptogen, plant, phytochemical, and plant-derived. Results : The most investigated medicinal herbs for their adaptogenic activity are Eleutherococcus senticosus, Panax ginseng, Withania somnifera, Schisandra chinensis, and Rhodiola spp., salidroside, ginsenosides, andrographolide, methyl jasmonate, cucurbitacin R, dichotosin, and dichotosininare are phytochemicals that have shown a considerable adaptogenic activity. Phytochemicals that have been demonstrated adaptogenic properties mainly belong to flavonoids, terpenoids, and phenylpropanoid glycosides. Conclusion : It is concluded that the main modes of action of the selected adaptogenic plants are stress modulatory, antioxidant, anti-fatigue, and physical endurance enhancement. Other properties were nootropic, immunomodulatory, cardiovascular, and radioprotective activities.
Our inflammatory response and innate immune systems started evolving two billion years ago—long before we humans—and our adaptive immune system—came into being. While the look back in time is useful and productive, epidemiologists and other scientists, who typically follow “lagging indicators,” now must do a better job of anticipating where problems will emerge and, to the extent possible, devising means for preventing them from developing. Unlike the 300,000 years since our emergence as a species and the hundreds of millions of years preceding that, during the Anthropocene epoch, humans have been the primary agents of massive ecological change. Global climate change has resulted in extreme pressure on means of food production. The consequent increase observed in the inflammatory capacity of ultraprocessed foods parallels the rising temperatures globally. With this as background, we make specific recommendations for additional research in areas we believe represent frontiers in the effort to understand and control chronic systemic inflammation including: deep emotional issues related to the chemical senses; amelioration of pain—both physical and mental; discrimination and other psychosocial stress; losses in agricultural productivity and nutrient adequacy in a hotter world; autoimmune diseases and food allergies; how coevolution with microbes can provide additional insight into inflammatory and immune responses; and looking outward and connecting back to global environmental crises to consider the Gaia Hypothesis as a framework for ecological regulation and homeostasis for a more sustainable world with lower overall inflammatory potential. Finally, we discuss the need to engage governmental actors, nongovernment organizations, and commercial entities in order to affect policy changes, marketing decisions, and even methods of conflict resolution in order to optimize making nutrition recommendations regarding both public health and personalized medicine.
This chapter presents an analysis of lymphocytes and host environment of young and aged mice for conditioned immunosuppression. The chapter presents a theory that suggests that conditioned immunosuppression of antibody responses in mice is the result of the interaction of suppressive factors, released within the milieu of the conditioned animal, with a potentially immunoregulatory T-cell population unique to conditioned animals. A useful model to study the role of neurohormones/neurotransmitters in conditioning may be the aging animal. In preliminary studies, inheritance of the conditionability trait was modified by cross-fostering on mothers preselected to show high or low activity in an open field. Most workers in this field agree on the importance of control of the environmental parameters within which studies are performed. However, little effort has been placed on analysis of the effect of deliberately varying those parameters.
This chapter discusses long-term effects of neuroendocrine–immune interactions during early development. The immune system is modulated by the central nervous system (CNS). The chapter presents a study that demonstrated a structural link between the nervous system and the immune system by observing the innervation of lymphoid tissue by noradrenergic and peptidergic fibers. In addition to altering immune responsiveness through autonomic nervous system projections, the CNS modulates bodily defenses through neuroendocrine activity. Many hormones that are under the control of the brain are capable of potentiating or diminishing certain measures of immune performance. These measures range from alterations in tumor rejection in vivo to changes in cell-mediated or humoral immunity in vitro. In addition to its immunoregulatory, antiviral, and antiproliferative effects, interferon is capable of modulating the neuroendocrine activity. Interferon used in treating certain hormone-dependent cancers based on evidence that estradiol, progesterone, and thyroxine are suppressed in normal women after interferon administration and that the secretion of testosterone is diminished in Leydig cells in vitro after incubation with interferon.
This chapter discusses the involvement of the central nervous system circuitry in the modulation of immune responses. The immune system is capable of modulating both neuroendocrine responses and behavior of the organism. Immunologically altered neuroendocrine and behavioral responses may affect immunity. The inescapable conclusion is the existence of a complex network that must expand the definition of a self-regulatory immune system. The data revealing bidirectional links between the nervous and immune systems question the notion of an autonomous immune system. The immune system is capable of considerable self-regulation, and, adopting classic reductionist strategies, immune responses can be made to take place in vitro, removed from the variability that characterizes integrated adaptive phenomena. The functions of the immune system that are of ultimate concern, however, are those that take place in vivo. The presence of receptors for cytokines, neurotransmitters, and hormones on cells of the immune system, the ready availability of these signal molecules in the lymphoid microenvironment, and the direct demonstration of functional bidirectional communication reveal a dynamic process of interaction between the nervous and immune systems with profound influences on the ability of an animal to respond to external and internal challenges, and to maintain homeostasis through bidirectional signaling.
This chapter focuses on some behavioral adaptations in autoimmune disease-susceptible mice. Cyclophosphamide, a potent immunosuppressive drug, has noxious gastrointestinal properties. Normal, healthy animals avoid consumption of solutions containing cyclophosphamide (CY), and they avoid distinctively flavored solutions that are associated with injections of the drug. When dissolved in chocolate milk, a highly preferred drinking solution for the mouse, animals show a dose-related decrease in consumption of the CY-laced solution. Nevertheless, at concentrations that will be consumed, lupus-prone mice with manifest symptoms of autoimmune disease drink more CY-laced chocolate milk than healthy, congenic control mice. Mice with active symptoms of disease drink sufficient amounts of the CHOC/CY solution to reverse their pre-experimental lymphadenopathy and reduce their elevated autoantibody titers. The immunologically derived changes that are immediately responsible for the death of the animals may not, in the time available, respond to the therapeutic effects of the low doses of CY that are consumed by these lupus-prone animals.
This study investigated the immune alterations induced in rats by an aversive conditioned stimulus (CS), which had been developed through pairings with electric shock. The results showed that the CS induced pronounced alterations of splenic lymphocyte function as indicated by a reduction in the mitogenic responsiveness to the T-cell mitogens concanavalin-A (Con-A) and phytohemag-glutinin (PHA) and the B-cell mitogen lipopolysaccharide (LPS), a reduction in interleukin-2 production, and a reduction in natural-killer-cell activity. The magnitude of the immune alterations was dependent on the time interval between the training and testing of the CS. There was little evidence of an immunomodulatory effect of the CS 1 day following training, but the effect developed as the interval between training and test was extended (3, 6, and 12 days). In contrast, a mitogen-stimulation assay using blood lymphocytes showed a reduction in the mitogenic responsiveness to Con-A and PHA that was comparable across the days following training. These results establish a time-dependent, compartment-specific, CS-induced immunomodulatory effect.
This chapter discusses physiological implications of the immune-neuro-endocrine network. Immunological cells are specialized to detect altered patterns of self-antigens and to recognize microorganisms and foreign macromolecules and particles. The immune system can be viewed as a spread-out organ with its cell components strategically distributed in the body. Immunological cells can bind antigens or participate in inflammatory reactions either locally in lymphoid structures or in the circulation. This process leads to the generation of effector cells or molecules that are able to interact with their specific targets. The capacity of the immune system to discriminate self and nonself is based on the wide range of specificities expressed by immune cells, a high proportion of which are directed toward antigenic recognition of modified self-cells or self-molecules. This characteristic implies that the immune system can perceive an internal image of body constituents and react to particular distortions of this image. After recognition of nonself and modified self through a wide diversity of receptors, activated immune cells convey messages to the brain or brain-controlled structures.