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Occurrence of DTH during the development of Arthus type sensitivity

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Abstract

Guinea pigs were injected in the footpads with either purified diphtheria toxoid or recrystallized egg albumin in Freund adjuvant without mycobacteria. Each guinea pig was then skin-tested only once with the specific antigen and bled for antibody determination. After injection of the sensitizing antigen, a latent period occurred during which neither sensitivity nor circulating antibody could be detected. A period of delayed sensitivity followed wherein circulating antibody could not be discerned and which could be transferred by lymph node cells. Ultimately, the Arthus type sensitivity developed, accompanied by circulating antibody. The duration and severity of reactions to homologous antigens during the last 2 phases varied with the antigen and with the dose. An increase in the sensitizing dose decreased the duration of the delayed type of allergy, a decrease in the dose prolonged the delayed type. Inclusion of mycobacterium in the sensitizing inoculum tended to introduce delayed sensitivity earlier and delay the onset of Arthus type sensitivity. When specific precipitate in antibody excess was included with the toxoid in the sensitizing dose, the onset of the Arthus phase was hastened. When lymph nodes from a large number of sensitized donors were removed during the latter part of the latent period, recipients of the cells showed a delayed type sensitivity.

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... Older studies, initiated in the 1950s, characterized some variables of immunization that differentially affect the generation of DTH and IgG antibody production (14)(15)(16). Exclusive DTH corresponds in mice to the exclusive generation of Th1 cells (4). IgG 1 antibody production exclusive of DTH corresponds to the generation of Th2 cells (4). ...
... Salvin showed that antigen dose, and time after immunization, affect the DTH/IgG antibody nature of the ensuing responses (14), see Figure 1A. Moderate doses first induce DTH and, with time, the response evolves toward an IgG mode, with minimal expression of DTH. ...
... In the presence of amounts of antigen leading to efficient B cell presentation, there will be robust CD4 T cell cooperation and the generation of Th2 cells. A sufficiently lower dose, leading to less efficient B cell presentation, will support only tentative co-operation, and the generation of Th1 cells, thus accounting for Salvin's observations on antigen dose (14). (iii) When a foreign antigen impacts the immune system, it initially causes CD4 T cells to multiply. ...
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How an antigen interacts differently with lymphocytes and other cells of the immune system, to result in the generation of distinct classes of immunity, is one of the most basic questions of immune regulation. Understanding the nature of these "decision criteria" is central to developing effective medical interventions. Clinical observations lead to the recognition that much disease is due to an inappropriate class of immunity being generated, inappropriate because damaging, as in autoimmunity and allergies, or inappropriate because ineffective, against pathogens and cancer. I argue that the prevalent, contemporary conceptual frameworks, employed to analyze the nature of the decision criterion controlling the Th1/Th2 phenotype of the immune response, are implausible, as they ignore pertinent, classical observations. I outline reasons for favoring a different framework, that takes these observations into account, and explore its pertinence to the design of strategies of medical intervention.
... Salvin, in the 1950s, examined how the dose of antigen administered affected the class of immunity expressed at different times following immunization. Figure 2 summarizes his conclusions [19]. Note that low doses generate an exclusive cell-mediated, DTH response; medium doses more rapidly generate a cell-mediated response that evolves, with time, into a humoral mode; the administration of even larger doses results in more rapid responses, sometimes resulting in a barely detectable cell-mediated phase. ...
... The study showed that low amounts of peptide generate Th2 responses and higher amounts generate Th1 responses. We were skeptical of the physiological relevance of these observations, partly because they were in contradiction with most in vivo observations, as illustrated by those of Salvin [19]. The culture conditions also seemed rather extreme in that they employed very high numbers of CD4 TcR transgenic cells per culture well. ...
... (2) A somewhat similar difficulty appears to exist in trying to understand why the dose of antigen, or the number of non-rapidly replicating organisms employed for infection, similarly determines the Th1/Th2 nature of the immune response. Again, the finding that lower doses or lower numbers induce Th1 responses and higher doses or higher numbers induce Th2 responses seems true of foreign, vertebrate antigens [19,21], that are not expected to contain any PAMPs, and of pathogens, including leishmania parasites [22] and mycobacteria [23,24], that contain a multitude of PAMPS. ...
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It is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, is often critically dependent on the class of immunity generated. Here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates Th1 or Th2 cells. We refer to this mechanism as the “decision criterion” controlling the Th1/Th2 phenotype of the immune response. A plausible decision criterion should account for the variables of immunization known to affect the Th1/Th2 phenotype of the ensuing immune response. Documented variables include the nature of the antigen, in terms of its degree of foreignness, the dose of antigen, and the time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. These are quantitative variables made at the level of the system. In addition, the route of immunization is also critical. I describe a quantitative hypothesis as to the nature of the decision criterion, referred to as the Threshold Hypothesis. This hypothesis accounts for the quantitative variables of immunization known to affect the Th1/Th2 phenotype of the immune response generated. I suggest and illustrate how this is not true of competing, contemporary hypotheses. I outline studies testing predictions of the hypothesis, and illustrate its potential utility in designing strategies to prevent or treat medical situations where a predominant Th1 response is required to contain an infection, such as those caused by HIV-1 and by Mycobacterium tuberculosis, or to contain cancers.This article is protected by copyright. All rights reserved.
... only few foreign epitopes) only having the potential to generate Th1, cell-mediated responses [26,27] . (2) The dose of more foreign antigens, with lower doses favouring the generation of cell-mediated, Th1 and higher doses favouring antibody, Th2 responses [28][29][30][31]. ...
... (3) The time after immunization at which the Th1/Th2 phenotype of the immune response is assessed. Most immune responses evolve from an exclusive or predominant Th1 mode to one having a significant and, with time, a larger Th2 component [28,29]. One well-recognized example follows infection with human immunodeficiency virus (HIV). ...
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We discussed different proposals for how the nature of the Th1/Th2 phenotype of an immune response is determined, and favored one, the Threshold Hypothesis, as plausible and so useful as the basis for further discussions. The activation of a target CD4 T cell can be facilitated by helper CD4 T cells when the CD4 T cells interact via an antigen-presenting cell (APC). The Threshold Hypothesis states that tentative and robust antigen-mediated CD4 T cell cooperation results in the target CD4 T cell respectively giving rise, upon activation, to Th1 and Th2 cells. We primarily discussed four topics. We briefly discussed in the background section certain limitations of the Th1/Th2 paradigm in understanding immune class regulation, and the remarkable anti-inflammatory properties of human IgG4 antibody. Secondly, we assessed the role of class II MHC molecules in determining the number of mature CD4 T cells and so affecting the Th1/Th2 phenotype of immune responses. We also discussed the controversial role of CD8 T cells in affecting the Th1/Th2 phenotype of responses to MHC and other antigens, and the potential role of their relative scarcity in neonates in biasing responses towards an antibody, Th2 mode. Lastly, we examined the regulation of the Th1/Th2 phenotype of both primary and on-going immune responses in the context of the intriguing proposal that antigen initially generates different classes/subclasses of immunity and then selects, by a feedback mechanism, the most effective class. We found this interesting idea difficult to reconcile with various observations. This article is protected by copyright. All rights reserved.
... Classical observations of the role of antigen dose on the type of immune response were made as early as the 1950s when Salvin immunized guinea pigs with either Diptheria toxin or the protein ovalbumin (OVA), and these animals displayed a delayed-type hypersensitivity (DTH) response to antigen [36]. This DTH response preceded the antibody response, and it was noticed that depending on the dose given, the length of the DTH response seen before progress to an antibody response would change. ...
... This DTH response preceded the antibody response, and it was noticed that depending on the dose given, the length of the DTH response seen before progress to an antibody response would change. High doses resulted in shorter DTH responses, while progressively lower doses eventually resulted in strictly DTH in immunized animals [36]. Further studies on the relationship between antibody production and DTH responses, which can be thought of in contemporary terms as cell-mediated or Th1 responses, led to the notion that these were inversely related. ...
Article
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Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and have been crucial for the development of therapeutics and vaccines that have been approved for human use. Most of these models use artificially high doses of virus, ensuring lethality in pre-clinical drug development studies. However, this can have a significant effect on the immune response generated. Here I discuss how the dose of antigen or pathogen is a critical determinant of immune responses and suggest that the current study of viruses in animal models should take this into account when developing and studying animal models of disease. This can have implications for determination of immune correlates of protection against disease as well as informing relevant vaccination and therapeutic strategies.
... In response to indications that conditions are challenging, individuals improve in surviving parasites and/or predators Exposure to higher levels of infection is indicative of more challenging conditions. Higher doses of infection have been found to increase antibody production in numerous species, including guinea pigs, sheep, and mice (Salvin, 1958;Wortis et al., 1966;Parish, 1972;Lagrange et al., 1974;Hernandez-Pando et al., 1997). ...
... Higher doses of infection are consistent with more challenging conditions. Higher doses of infection also increase antibody production in numerous species, including guinea pigs, sheep, and mice (Salvin, 1958;Wortis et al., 1966;Parish, 1972;Lagrange et al., 1974;Hernandez-Pando et al., 1997). ...
Preprint
Background: Solon (2019) introduced genetic bandwagoning in a very general sense: A variant sequentially 1) evaluates its holder’s quality and 2) induces its holder to relinquish resources if the holder’s quality is low. Here, I introduce a more complex form of bandwagoning in order to account for a series of phenomena considered “paradoxical” by scientists specializing in their literatures: a) depression, b) differential nurturing, c) honest signaling of quality, d) reproductive suppression, e) stress-induced anthocyanins, and f) hormesis. These literatures are characterized by the following findings: 1) Low-quality individuals incur a cost against reproductive success compared to higher-quality individuals. 2) Individuals not (yet) identified as low-quality incur a cost against their ability to survive predators and/or parasites compared to individuals that have already been identified as low-quality. 3) Females incur a cost against reproductive success compared to males. 4) Males incur a cost against their ability to survive predators and/or parasites compared to females. 5) If conditions are challenging, individuals gain in both reproductive success and their ability to survive predators and/or parasites compared to less challenging conditions; however, too-challenging conditions detract from both. For each literature, at least one of these findings is unaccommodated by existing theory when considered in the context of that literature. Despite existing theory, these patterns are remarkably persistent. Question: Can paradoxes fitting these patterns be explained by genetic bandwagoning theory? Conclusion: Here, reservation is introduced as a form of bandwagoning in which a bandwagoning variant induces its holder to reserve from (i.e., withhold) some of its ability to survive parasites or predators. Reservation would occur for the purpose of assessing a holder’s quality when conditions are sufficiently unchallenging that few individuals are chronically stressed, so it is otherwise difficult to evaluate a holder’s quality. If the holder is subsequently killed, wounded, or infected, then it is identified as lacking the quality that would allow its descendants to survive more challenging conditions. The holder loses some or all of its resources as a direct consequence of the very death, wounding, or infection that identified its low quality. That is, in reservation, the two steps of bandwagoning are accomplished simultaneously. (This way of bandwagoning is distinguished from when the two steps are accomplished sequentially, which is termed resonation.) Reservation shares numerous premises with Zahavi’s handicap principle. If conditions are challenging, individuals would downregulate reservation and also be less likely to forego resources through resonation (which accounts for (5)). Additionally, a bandwagoning variant would likely evolve to vary the reservation it induces from holder to holder as a hedge against the possibility that conditions suddenly turn severe before it can adjust the reservation. Individuals already identified as low-quality would downregulate reservation (which accounts for (2) above) and would instead forego resources through resonation (which accounts for (1)). Additionally, females would downregulate reservation (which accounts for (4)) and, as a consequence, surviving females are more likely than surviving males to forego resources through resonation (which accounts for (3)).
... Immunizing with a higher dose of antigen results in a qualitatively similar response but with a faster tempo. Immunization with a lower dose results in a slower immune response, and often only a cell-mediated phase occurs [18,19]. These generalizations seem true under diverse circumstances, even when immunization is by different routes [20]. ...
... Now consider an individual, individual 3, with a transition number of 1000 N. We would expect this individual to rapidly make a cell-mediated response when the bacterial load is close to but below the transition number, say100 N. However, it appears to be a general rule that lower doses of antigen, below that that generates an optimal cell-mediated response, generates such a response considerably less efficiently [18]. Thus the race between the growth of bacteria, ...
Article
Most people infected by Mycobacterium tuberculosis, about 90%, contain the pathogen and are healthy. Most investigators have concluded that pathogen‐specific Th1 cells contribute to protection. Pulmonary tuberculosis, the most prevalent form of disease, is associated with destructive granulomas, the formation of which also appears to involve Th1 cells. In what sense then do the two Th1 components of the response, in healthy infected individuals and patients, differ? An insight to this question might provide clues for attaining effective vaccination and better treatment. We approached this question by examining the relative prevalence of different IgG isotypes among anti‐mycobacterium specific antibodies in patients and healthy infected individuals as a surrogate marker for the Th1/Th2 phenotype of the response. Our observations lead us to agree that healthy infected individuals generate a predominant Th1 response. Our observations also lead us to propose that many patients make a similar kind of response as healthy infected individuals, but that this response is too weak to contain the infection. We refer to such individuals as having type I tuberculosis. Other patients appear to have a greater and detrimental Th2 component to their immune response than that of healthy infected individuals. We refer to these individuals as having type II tuberculosis. This proposal, that there are two types of tuberculosis, reflecting two distinct types of failure by the immune system, will, if correct, be pertinent to vaccine design, treatment of tuberculosis, and in making further progress in our understanding the genetics of susceptibility to M tuberculosis. This article is protected by copyright. All rights reserved.
... A classic study by Salvin of the late-1950s delineated how the dose of antigen, and time after immunization, affects the cell-mediated/IgG nature of the response [11]. Salvin measured DTH to assess cell-mediated immunity, and IgG antibodies to assess the humoral component of the response. ...
Article
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Koch attempted to treat tuberculosis in the late 1800s by administering an antigenic extract derived from the pathogen to patients. He hoped to bolster the patient’s protective immunity. The treatment had diverse results. In some, it improved the patient’s condition and in others led to a worsening state and even to death. Koch stopped giving his experimental treatment. I consider here three issues pertinent to realizing Koch’s vision. Rational immunotherapy requires a knowledge of what constitutes protective immunity; secondly, how on-going immune responses are regulated, so the patient’s immunity can be modulated to become optimally protective; thirdly, a simple methodology by which treatment might be realized. I deliberately cast my account in simple terms to transcend barriers due to specialization. The proposed immunotherapeutic treatment, if realizable, would significantly contribute to overcoming problems of treatment posed by antibiotic resistance of the pathogen.
... In vivo, low and higher doses of protein Ag or pathogens give rise to Th1 and Th2 cells, respectively. Furthermore, it is known that the immune response to diverse Ags, both living and nonliving, often goes through an exclusive Th1 phase before a Th2 component develops (67). Both the effect of Ag dose on the Th1/Th2 phenotype of the immune response as well as the evolution of the immune response from a Th1 to a Th1/Th2 mode with time are understandable in terms of the mechanism outlined in this study. ...
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Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.
... Recent publications have reported the development of a form of delayed skin reactivity following injection of small amounts of protein antigens in Freund's adjuvant (14), and that this reaction is diminished, but not completely suppressed, in guinea pigs by 200 r total body x-irradiation (15). Development of the delayed sensitivity is followed by production of antibody, a response which is suppressed by 200 r total body x-irradiation (15,16). ...
Article
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1. In guinea pigs, aminomethylpteroylglutamic acid (methotrexate) is capable of blocking the development of delayed skin hypersensitivity, the primary antibody response, and the specific febrile response to ovalbumin and diphtheria toxoid. The primary antibody response is more easily inhibited than is the development of delayed skin hypersensitivity. 2. The effect of methotrexate on immunologic responses depended upon the dose of methotrexate employed and the strength of the antigenic stimulus.
... The common sites must be larger than is required for a humeral cross reactive response.In the early sixties the presence of histocompatibility antigens that can cross react with antigen(s) of group A streptococcal membrane was found in dogs, rabbits, guinea pigs, rats, and mice, as well as in man (RAPAPORT et al.,t972). These observations provide evidence 7t that a significant number of histocompatibility (SALVIN, 1958). Circulating antibodies remain absent in those cases. ...
... The ability to show Arthus reactions, however, did not appear at the same time as detectable circulating antibody, since of 66 animals that had circulating antibody from the 7th to the 16th day postsensitization, only 39 developed Arthus reactions on intradermal injection of 1 Lf toxoid. These results are in striking contrast to the course in adults in which after sensitization with 1 Lf toxoid in Freund's adjuvant (with or without mycobacteria), delayed hypersensitivity can be detected on the 4th day, and both Arthus reactions and circulating antibody simultaneously on the llth to 14th day (2). Neonatal guinea pigs thus seemed less reactive than adults during both the delayed and Arthus phases. ...
Article
Neonatal guinea pigs during the first 2 weeks of life did not indicate the presence of delayed hypersensitivity intradermally, after sensitization with purified soluble antigens in dose levels that induced detectable delayed hypersensitivity in the skin of adults. Although Arthus type allergy was detectable in newborns, circulating antibody frequently preceded its appearance by several days. Passive Arthus reactions were not produced in newborns as readily as in adults. Contact hypersensitivity and allergic encephalomyelitis were induced in newborns, but corneal reactions were not. Total body irradiation with 200 r inhibited antibody formation in newborns, as in adults. In addition, the induction period for anamnestic responses in newborns and the antigen elimination rate were the same as in adults. Passive transfer of delayed hypersensitivity from sensitized newborns to normal adults was accomplished.
... However, good evidence exists for the role of sensitized mononuclear cells in the pathogenesis of this reaction. It is possible to transfer cutaneous basophil hypersensitivity reactions with sensitized lymph node cells but not with serum (29), and the reactions in the recipient have the basophil infiltrate described here. 2 The reaction is inhibited by antilymphocyte serum and has antigenic requirements for the expression of skin test reactivity similar to that of delayed hypersensitivity (5,6). ...
Article
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Delayed onset erythematous skin reactions elicited in guinea pigs early in the course of sensitization with azobenzenearsonate-protein conjugates or with protein antigens in incomplete Freund's adjuvant or in saline were found to have a characteristic morphology which sets them apart from delayed hypersensitivity and the classic antibody mediated reactions. The principle feature was massive dermal infiltration with basophilic leukocytes. Mononuclear cells of several types including activated and small lymphocytes, monocytes, macrophages, and blast cells were also present. Such reactions have in the past been designated Jones-Mote hypersensitivity, but we prefer the descriptive term cutaneous basophil hypersensitivity (CBH) for the reasons given. Occasional basophils extruded their granules, and individual granules, retaining their characteristic ultrastructure, were commonly seen in the interstitium. However, intercellular junctions between endothelial cells were closed except during cell emigration and there was no morphologic evidence of an histamine-like effect. The majority of basophils, moreover, did not degranulate but underwent nuclear pyknosis and cytoplasmic degeneration and were phagocytosed by macrophages. Phagocytosed basophil granules retained their ultrastructure. Skin tests performed at late intervals after sensitization had a different time course and morphology. Animals sensitized with protein antigens in complete Freund's adjuvant developed delayed hypersensitivity; however, reactions elicited in such animals at early (but not late) intervals after sensitization contained a prominent basophil component. We interpret such reactions to be a mixture of delayed hypersensitivity and cutaneous basophil hypersensitivity. The function of the basophil in CBH and its relation to the mononuclear cells which accompany it are unknown, and various possibilities are discussed. We conclude that cutaneous basophil hypersensitivity is a distinct immunologic and morphologic entity, occurring early in the course of sensitization with protein antigens incorporated in any of several vehicles. The mechanism of the reaction is presently unknown, and a general hypothesis to explain its pathogenesis has been proposed.
... This hypothesis readily explains the observation that the specificity requirements for antibody tolerance and delayed hypersensitivity are much lower than those required for antibody formation. It is also consistent with the observation that low doses of antigen preferentially induce cell-mediated immunity (26) and antibody tolerance (37), whereas particulate antigens (e.g., pol)maerized flagellin) preferentially develop humoral antibodies. SUMMARY Flagellin (mol.wt. ...
Article
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High and low zone antibody tolerance to bacterial flagellin can be induced in adult strain W Wistar rats by multiple injections of a cyanogen bromide (CNBr) digest of flagellin at two widely spaced dose levels. Intermediate doses of the CNBr digest produce enhanced antibody titers to flagellin rather than antibody tolerance. Studies reported in this paper revealed that both high and low zone antibody tolerance to flagellin were accompanied by heightened levels of delayed-type hypersensitivity. Conversely, when enhancement of the antibody response occurred, suppression of delayed hypersensitivity was observed. This inverse relationship between humoral and cell-mediated immunity was very striking in strain W Wistar rats but was not quite so clear-cut in another strain of Wistar rats (strain J). Strain J rats were resistant to the induction of antibody tolerance and gave higher immunological responses to flagellin than strain W animals. In addition, it was observed that, in contrast to adult tolerance, administration of the CNBr digest to neonatal rats induced complete tolerance at the level of both humoral and cell-mediated immunity. These findings were discussed in the light of earlier studies with flagellin and provide further evidence for a previously described hypothesis.
... Salvin's observations show that the generation of DTH does not inevitably lead to an inhibition of antibody responses. It is difficult to mimic the effects, upon the immune system, of slowly replicating F I G U R E 3 (A) The dependence of DTH and IgG antibody responses on antigen dose and time after immunization Based on observations described in ref. 49 (B) Observations illustrating the phenomenon of low-zone cell-mediated immune deviation. Different mice or rats were given a series of injections of different amounts of antigen, as indicated by pretreatment dose, and then given a challenge of antigen that, in untreated rodents, results in antibody production. ...
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We propose a treatment of HIV‐1+ individuals designed to harness protective immunity, lead to viral containment, and so render the individual minimally infectious. A few HIV‐infected individuals, “elite controllers”, generate a stable Th1, cytotoxic T lymphocyte response that contains the virus. Most infected individuals, in the absence of therapy, first generate a similarly protective response that evolves with time a Th2 component, associated with antibody production and loss of viral control. Cessation of anti‐retroviral treatment after three years results in viral rebound in most, but about one in seven individuals contains the virus, so‐called post treatment controllers. We suggest an understanding, of how the Th1/Th2 phenotype of immune responses is controlled, can explain these different outcomes, and leads us to propose a non‐invasive, personalized strategy of immunotherapy. We propose that monitoring the relative prevalence of HIV‐1 specific IgG1 and IgG2 antibodies can provide a biomarker for deciding when to interrupt/withdraw anti‐retroviral therapy to optimally harness protective immunity.
... 21 It has also been demonstrated that the initial T-cell response magnitude and subsequent development and retention of memory T cells are directly related to the antigen dose, 22 and that limiting the antigen dose increased CD4 T cell memory development. 14 Of high interest, a very complex interplay between many of the above-mentioned effects of antigen dosing has been reported to determine the severity of autoimmune disease. Notably, higher antigen doses can lead to deletion of autoreactive T cells and thus improve autoimmune outcome in autoimmune encephalomyelitis, 15 whereas in a dust mite model, oral delivery of low dose antigen was the most effective regimen to prevent autoimmunity. ...
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During the past 3–4 decades, an increasing amount of evidence has pointed to the complex role of the antigen dose or T cell receptor (TCR) stimulation strength on the subsequent type, duration and “flavor” or quality of the response. Antigen dose was initially shown to impact Th1/Th2 bias, and later also shown to differentially affect development and induction of Tregs, Th17, T-follicular helper (Tfh), cells, and others. In recent years the quality of both CD4/8 T cells during infections, cancer and/or autoimmunity has turned out to be critical for subsequent disease outcome. Importantly, different vaccination strategies also lead to different types of T cell responses, and the role of the antigen dose is emerging as an important factor as well as a tool for investigators to utilize in fine-tuning vaccine efficacy. This commentary will highlight essential background of how antigen dose can impact and affect the quality of T cell responses, and discuss how this translates in different vaccine settings.
... Vaccines can contain different amounts of target antigen; however, it is not well known how the antigen dose influences the quality of a resulting immune response. Relatively few studies directly investigate this, although an inverse relationship between antigen dose and the duration of delayed type hypersensitivity has been proposed [1]. Also, it has been hypothesized that more T cells and antigen are required for Th2 than Th1 responses [2]. ...
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The relationship between the antigen dose and the quality of an immune response generated upon immunization is poorly understood. However, findings show that the immune system is indeed influenced by the antigen dose; hence underlining the importance of correctly determining which dose to use in order to generate a certain type of immune response. To investigate this area further, we used Göttingen minipigs as an animal model especially due to the similar body size and high degree of immunome similarity between humans and pigs. In this study, we show that both a humoral and a cell-mediated immune (CMI) response can be generated following intraperitoneal immunization with tetanus toxoid (TT) formulated in the CAF09 liposomal adjuvant. Importantly, a low antigen dose induced more TT-specific polyfunctional T cells, whereas antigen-specific IgG production was observed upon high-dose immunization. Independent of antigen dose, intraperitoneal administration of antigen increased the amount of TT-specific cytotoxic CD8β⁺ T cells within the cytokine-producing T-cell pool when compared to the non-cytokine producing T-cell compartment. Taken together, these results demonstrate that a full protein formulated in the CAF09 adjuvant and administered to pigs via the intraperitoneal route effectively generates a cytotoxic T-cell response. Moreover, we confirm the inverse relationship between the antigen dose and the induction of polyfunctional T cells in a large animal model. These finding can have implications for the design of upcoming vaccine trials aiming at establishing a cytotoxic T-cell response.
Article
1) A subcutaneous injection of hamster erythrocytes (HRBC) in Freund's complete adjuvant (FCA) or an intravenous injection of hamster lymph node (HLN) cells suppressed antibody production against HRBC in the low-responder C57BL/6 and AKR mice, when HRBC in saline were given on the same day; 2) The suppressing effect of such treatments was neither detectable in the high-responder SL mice, nor in the C57BL/6 mice, which had been pre-sensitized with HRBC in FCA or hamster lymphoma cells; 3) Positive reactions of the peritoneal macrophage disappearance test and the enhanced antibody production were detected seven days after treatment with HRBC in FCA and HRBC in saline, or HLN cells and HRBC in saline; 4) The suppressing effect of such simultaneous treatments on anti-HRBC antibody production was eliminated by a transfer of normal syngeneic thymus cells to AKR mice or a transfer of thymus cells from SL to C57BL/6 mice. Suppression of the antibody production in the low-responder mice by the described simultaneous treatments may be due to a competitive involvement of HRBC-specific thymus-derived cells (T cells) in the developmental stages of delayed hypersensitivity and antibody production. High-responder SL mice appear to have enough T cells for development of the delayed hypersensitivity and as helper cells in antibody production. These results appear to support the concept that T cells for delayed hypersensitivity and antibody production to HRBC antigen are derived from the same original pool.
Article
The experimental sections of this study have demonstrated that neonatal guinea pigs injected with homologous testicular homogenate combined with adjuvant undergo aspermatogenesis after they reach maturity. Sensitization thus occurs early and there is an early release of circulating body. Seminiferous differentiation and spermatogenesis, however, are neither inhibited nor prevented, but testicular destruction follows later. Both testes of a pair tend to respond alike as to timing and severity of lesions; unilateral castration during neonatal or adolescent stages has no effect on the aspermatogenic response of the remaining testis. Histologically normal testes, removed from sensitized animals, induce aspermatogenesis and the release of circulating antibody in mature recipients, but damaged testes from sensitized animals fail to do so.
Article
Delayed hypersensitivity of the classic tuberculin type can be induced in mice by single injection of tuberculoprotein, chicken ovalbumin, or bovine serum albumin in water-in-oil emulsion containing no mycobacteria. Including mycobacteria in the emulsion does not affect the course of sensitization to either tuberculoprotein or ovalbumin but does hasten, without increasing, sensitization to bovine serum albumin. Development of immediate hypersensitivity seems to pursue a course independent of that followed by delayed hypersensitivity. More efficient delayed hypersensitization is achieved by intracutaneous vaccination than by other routes, but aqueous solutions of antigen injected, even by this route, fail to induce delayed hypersensitivity; aqueous suspensions of tubercle bacilli are weakly allergenic. Minimum quantities of protein antigens injected in water-in-oil emulsions which are required to sensitize 50 per cent of vaccinated mice fall within the range of 0.01 to 1 μg.
Article
THE existence in the rabbit of genetically determined antigenic differences (‘allotypes’) among homologous γ-globulins has been described by Oudin, who succeeded in preparing precipitating antisera against them after prolonged immunization with specific immune precipitates in adjuvants1. Considerable work has been done in an attempt to define the number of distinct serological groups and the number of genes controlling them in the rabbit2. The allotypic groups have been reported to be located on fragments I and II (as defined by R. R. Porter) of γ-globulin digested with papain3.
Chapter
Surgery, radiotherapy, and chemotherapy are the principal modalities of treatment of cancer. Each is chosen in accordance with the type and stage of the disease, and each has its benefits and risks. Although radiotherapy and chemotherapy have the advantage of reaching tumors and cells that are inaccessible to surgery (or, because of their location or wide dissemination, that cannot be surgically removed), these forms of treatment may exert damaging effects on organ systems outside the intended targets. The lympho-reticular system is usually affected and as a consequence the immune mechanism may become impaired. In the past, immunologically compromised patients have often succumbed to the onslaught of severe infections even though their tumors were being restrained or eradicated by the therapeutic intervention. Fortunately, information about toxic and immunosuppressive effects of various therapeutic agents, the introduction of new agents in recent years, and the development of combinations of drugs have made possible more prudent utilization of these agents for maximal therapeutic benefits with relatively minimal undesirable effects. Nevertheless, chemotherapy and extensive radiotherapy continue to pose risks to the patient and further improvements in the management of cancer patients will in large measure depend on the acquisition of more knowledge about the effects of old and new therapeutic agents.
Article
Golden hamsters were used as hosts in this work, and mice of various strains as donors of antigens. 1) There were no strain differences in immunogenicity of erythrocytes from C57BL/6, AKR, SL and CF1 mice. 2) Primary intravenous immunization with mouse erythrocytes (MRBC) induced the production of hemolysin plaque-forming cells (PFC) in a large number, but elicited only in a negligible titer production of 2-mercaptoethanol-resistant antibody. 3) 2-Mercaptoethanol-resistant antibody was produced more efficiently in hamsters pre-sensitized with mouse lymph node (MLN) cells rather than those pre-immunized with MRBC after a booster with MRBC. 4) Numbers of PFC in pre-sensitized hamsters were three-times that of the non-sensitized hamsters after a booster with MRBC, when pre-sensitization was performed intradermally with a small number of MLN cells. 5) Average diameter of the hemolysin plaques in pre-sensitized hamsters was one and a half times larger than that in non-sensitized hamsters. Conclusions agree well with the results in our previous papers that the reversed combination of hosts and antigen donors employed support the concept that certain processes required for delayed hypersensitivity contributed to antibody production under a condition suitable for antibody response.
Article
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Immunological memory may not represent a special characteristic of lymphocytes but simply re£ect low-level responses driven by antigen that is re-encountered or persists within the host. T-cell memory is important to control persistent infections within the individual host and cannot be transmitted to o¡spring because of MHC polymorphism and MHC-restricted T-cell recognition. In contrast, antibody memory is transmissible from mother to o¡spring and may function essentially to protect o¡spring during the phase of physiological immuno-incompetence before, at and shortly after birth. This physiological immuno-incompetence is a result of MHC polymorphism and the dangers of the graft-versus-host and host-versus-graft reaction between mother and embryo, which necessitate immunosuppression of the mother and immuno-incompetence of the o¡spring. One may argue therefore that immunological memory of transmissible immunological experience is the basis on which MHC-restricted T-cell recognition could develop or coevolve.
Article
In a search for the source of the circulating endogenous pyrogen (EP) that mediates tuberculin-induced fever, tuberculin was incubated in vitro with various tissues of rabbits sensitized by intravenous infection with BCG. Evidence was obtained that tuberculin specifically stimulates cells in the blood of sensitized rabbits to generate pyrogen in vitro, whereas both lymph node and spleen cells from the same donors were inactive. Since normal blood cells, incubated in plasma of sensitized donors, were similarly activated, it is postulated that circulating antibodies play a role in sensitizing cells (presumably granulocytes) to release pyrogen on contact with tuberculin) both in vitro and in vivo. Release of endogenous pyrogen in vitro may be a sensitive means of detecting immunologic reactions between antigen and specifically sensitized blood cells-in other allergic states accompanied by fever.
Article
Adult guinea pigs were made unresponsive to a heterologous protein (e.g. bovine gamma globulin, or BGG) or a hapten-protein conjugate (e.g. p-aminobenzoic acid-bovine gamma globulin, or PABAγmiddot;BGG) by intraperitoneal injection of 80 mg cyclophosphamide and the specific antigen. This immunologic unresponsiveness developed to the specific antigen administered simultaneously with the cyclophosphamide, and not to any variants. Thus, animals unresponsive to PABAγmiddot;BGG remained unresponsive to the original antigen on challenge with a variant, but formed delayed hypersensitivity and circulating antibody to the variant. The specificity of immunologic unresponsiveness, therefore, seems more closely related to the whole antigen molecule than does delayed hypersensitivity.
Article
Full-text available
Jones-Mote reactivity, defined as a delayed-type skin reaction, occurs transiently early in the course of immunization with protein antigens or hapten conjugates with or without the adjuvant effect of tubercle bacilli. The skin reaction is typically a flat, well-circumscribed erythema with little induration beginning at about 6 hr, reaching a peak at 18–24 hr, and fading or gone at 48 hr. Immunogenic carrier requirements for hapten-specific Jones-Mote hypersitivity resemble those of antibody production rather than of classic delayed hypersensitivity. Skin test antigen requirements indicate that the Jones-Mote reaction involves an active stimulatory response rather than combination with preformed antibody, since ABA conjugates of nonimmunogenic D-polymers do not work. Studies with ALS and carrageenan suggest that the lymphocyte is an important contributor to the reaction, but the macrophage is not. Because the reactions studied here are operationally different from those described by Jones and Mote and because they have a characteristic histology, the term "cutaneous basophil hypersensitivity" is proposed.
Article
Injection of a small bacteriophage ϕX 174 into guinea pigs results in an accelerated elimination of phage detectable as early as 24 hours after injection. The immune nature of the accelerated elimination is indicated by its specificity, by the appearance of excess specific serum antibody after phage elimination, and by the prevention of accelerated elimination by 400 r whole body x-irradiation of guinea pigs prior to injection of phage. The early antibody response is considered to be a primary one since an analogous response occurs in newborn guinea pigs, antibody is not detectable in the sera of non-immunized animals, and the second challenge with ϕX stimulates a serum antibody response 100-fold greater than that after primary immunization. The early detection of immune elimination appears to be due, in part, to the small amounts of phage employed, since larger doses of phage delay the time of onset of detectable immune elimination. The early rise of serum antibody in the primary and secondary response appears exponential with a similar rate constant of antibody formation. The rate constant is also independent of dose. These findings have led to the suggestion that during this exponential phase, the relative rate of antibody formation at a cellular level may be constant for a given antigen.
Article
Atopic and nonatopic subjects were exposed intranasally to a protein antigen, and observations were made on the development of skin reactivity of the immediate type, the occurrence of symptoms, and the appearance of skin-sensitizing capacity in the serum. These were induced exclusively or with greater frequency in the atopic group, and this was not attributable to antigen administered in the course of skin testing.Four among 10 nonatopic individuals developed delayed-type skin reactivity which was not observed among the atopic subjects.The ABO blood group secretor status was observed with equal frequency in allergic and nonallergic individuals and was unrelated to appearance of skin reactivity.It is suggested that atopic individuals differ from nonatopic in having a greater mucosal permeability to inhaled antigens.
Article
Theiler's murine encephalomyelitis virus (TMEV) produces a chronic, inflammatory demyelinating disease in susceptible mouse strains that is used as a model for multiple sclerosis. Because disease susceptibility correlates temporally with the development of virus-specific delayed-type hypersensitivity (DTH) responses, we studied methods and mechanisms by which virus-specific DTH could be specifically inhibited. The intravenous injection of UV-inactivated TMEV coupled to syngeneic splenocytes via a carbodiimide linkage (TMEV-SP), prior to immunization, induced a significant degree of tolerance in virus-specific helper (Th) cells as determined by decreased DTH and T cell proliferative responses, and decreased interleukin (IL)-2 and interferon (IFN)-gamma protein and mRNA levels. In contrast to the reduced levels of Th1-specific lymphokine mRNA levels, IL-4-specific mRNA levels in response to virus stimulation were not affected in tolerant mice. Surprisingly, the total anti-TMEV antibody response in DTH tolerant mice was enhanced 20-100-fold over sham-tolerized controls and was composed of reduced levels of anti-virus IgG2a, but dramatically increased levels of anti-virus IgG1. The "split-tolerance" was antigen specific, dependent on the concentrations of TMEV and carbodiimide used in the coupling procedure, and varied with the number of coupled syngeneic splenocytes administered. The fixative effects of carbodiimide on antigen-presenting function were necessary for the induction of DTH tolerance with TMEV-SP, since intravenous administration of virus coupled to splenocytes via a biotin-avidin linkage led to enhanced virus-specific antibody responses, but was unable to inhibit DTH unless concomitantly fixed with carbodiimide. Collectively, the data indicate that Th1 cells (mediating DTH, IL-2 and IFN-gamma production, and helper function for IgG2a production) were specifically anergized, with concomitant stimulation of Th2 cells (producing IL-4 and mediating helper function for IgG1 antibody production).
Chapter
There is some reliable evidence that shows the presence of a resistance to cancer intrinsic in a human body, such as the correlation between senility and cancer incidence, the low metastatic rate against the number of tumor cells in blood flow, and the spontaneous cure of cancer observed in some cases. To clarify the mechanism of this resistance and to find a substance that would increase this resistance seems to be one of the important means in opening a way for new therapy in the treatment of cancer.
Chapter
The term “delayed hypersensitivity” may be defined as an immunologically specific inflammatory reaction slowly evolving at the site of injection of antigen. The reaction usually becomes apparent grossly only after several hours. The gross appearance with erythema and induration reaches a maximum at 24 to 48 hr. Histologically, the reaction is characteristic, being composed predominantly of lymphocytes and macrophages. Because of a difficulty in distinguishing between certain lymphocytes and macrophages in routine histolotical sections, they are often collectively referred to as mononuclear cells.
Article
Die nähere Erforschung des immunologischen Adjuvanseffektes und seine ausgedehnte Verwendung für die Immunisierungspraxis setzte nach den grundlegenden Veröffentlichungen von Ramon (1925a—c), Ramon und Descombey (1925a,b) und Glenny und ihren Mitarbeitern (1926) ein. Den Anstoß zu Ramons Untersuchungen hatten einige Beobachtungen an Pferden, die zur Antitoxingewinnung immunisiert worden waren, gegeben. Derartige Pferde hatten, wie es schien, überzufällig häufig, dannbesonders hohe Antitoxinkonzentrationen erreicht, wennam Applikationsort der Antigene lokale entzündliche Veränderungen auf getreten waren. Um diesen Zusammenhang zu prüfen, suchte Ramon nach Substanzen, die er Toxoiden (Anatoxinen) beimischen konnte und die sowohl die begrenzten lokalen entzündlichen Veränderungen als auch eine Steigerung der Antitoxinkonzentration im Blut bewirkten. Von den verschiedenen untersuchten Stoffen erwies sich ihm pulverisiertes, sterilisiertes Tapioca als besonders geeignet. Sowohl bei der Gewinnung des Diphtherieantitoxins als auch des Tetanusantitoxins wurden bei Verwendung von Tapioca Antitoxinkonzentrationen im Blut der Pferde erreicht, die um ein Vielfaches höher lagen als jene Titer, die durch die gleichen Mengen Anatoxin allein zu erzielen waren. Sehr bald erwies sich dann Tapioca auch bei anderen Antigenen als wirksames Adjuvans (Ramon et al. 1937, 1938, 1939).
Chapter
This chapter discusses the relation of delayed hypersensitivity to simple protein antigens and defines delayed reaction as an immunologically specific inflammatory reaction, which takes some hours to reach a maximum, occurring in the absence of demonstrable antibody of the conventional type. It discusses the relationships of contact sensitivity and delayed sensitivity to antibody production and describes several methods of producing pure delayed hypersensitivity to simple proteins in guinea pigs. Further, it describes the characteristics of the state of delayed hypersensitivity, including histology and physiopathology, passive transfer, effects of irradiation, systemic reaction, desensitization, Hodgkin's disease, and status of the homograft reaction. It reveals that delayed hypersensitivity is a stage in the production of antibodies. It is shown that delayed hypersensitivity reactions are observed in the course of immunization with protein antigens in animal species that are best capable of exhibiting this type of immune reactivity, guinea pig, and man.
Book
This much expanded second edition of A History of Immunology continues the tradition of the highly successful previous volume. It provides unparalleled insight into the concept of immunity and the field into which it has developed and examines how changing concepts and technologies have affected the course of the science. Each chapter examines an important facet of this discipline that has been central to the development of modern biomedicine. Fascinating stories of scientific disputes and shifting trends reveal how the personalities of scientists as well as political and social factors have played a role in the development of both theory and practice of immunology over time. Special features of the book include a biographical dictionary of important scientists and details of the many Nobel Prize-winning contributions of immunologists. All those interested in infectious disease and the historical context of science will enjoy this eloquent work. Book jacket.
Article
The widely accepted Cytokine Milieu Hypothesis proposes that the cytokine milieu, in which antigen activates CD4 T cells, from a non‐T cell source, primarily determines the Th subset to which the ensuing effector Th cells belong. We focus on the generation of Th1 and Th2 cells. We briefly restate the grounds for the Threshold Hypothesis we favor for how the Th1/Th2 phenotype of a response is primarily determined: tentative and robust thresholds of antigen‐mediated CD4 T cell interactions lead to the generation of Th1 and Th2 cells. The component antigens of pathogens are present in different amounts. It is expected, within the context of the threshold mechanism that, although there is often an initial predominance of Th1 or Th2 cells, some Th cells of the opposing type are initially generated. An initially somewhat heterogeneous Th response is known to become with time more “coherent” in its Th1/Th2 phenotype. I propose The Cytokine Implementation Hypothesis as a mechanism for how coherence is achieved. Most cytokines made by Th cells of one subset tend to facilitate the further generation of Th cells of this subset and/or inhibit the generation of Th cells of opposing subsets, accounting for how coherence may be achieved. Many observations on which The Cytokine Milieu Hypothesis is based are accounted for by this alternative hypothesis. We outline predictions of the new hypothesis and discuss the importance of coherence of immune responses for their efficacy in protecting against foreign invaders.
Article
Full-text available
Antigen-mediated stimulation of thymidine incorporation was demonstrated in lymph node cells from guinea pigs immunized with 100 µg human serum albumin in either Freund's incomplete or Freund's complete adjuvant. Animals receiving HSA in IFA exhibited both cutaneous basophil (Jones-Mote) hypersensitivity and lymphocyte stimulation at 1, but not at 6 wk after immunization. Significant stimulation required ≥ 10 µg HSA/ml of culture. Sensitization with HSA in CFA produced delayed hypersensitivity and permitted lymphocyte stimulation at both 1 and 6 wk. Stimulation was observed with as little as 0.1 µg HSA/ml at the later interval. Administration of 5 mg HSA intravenously at the time of sensitization with 100 µg HSA in IFA reduced but did not eliminate both CBH and lymphocyte stimulation at 1 wk. Antigen-specific inhibition of macrophage migration could be demonstrated with exudates from animals immunized with HSA in CFA, but not with HSA in IFA at 3 wk after sensitization. HSA was cleared from depots of CFA and IFA at similar rates, but significantly more antigen appeared in the plasma and subsequently in the draining lymph nodes following administration in IFA. Conversely, accumulated antigen disappeared more rapidly following CFA immunization.
Article
The effects of the route of injection and adjuvants on the immune response of guinea pigs were investigated at various stages of immune response to tetanus toxoid. Delayed-type hypersensitivity (DH) was observed as the first immune response to the toxoid before initiation of antitoxin production. The DH reaction was weak when plain toxoid was administered subcutaneously. Water-in-oil in water (w/o/w) enhanced greatly the reactivity of the immunized animals; pertussis vaccine, endotoxin and aluminium showed adjuvanticities in this order. The foot pad (fp) injection of plain toxoid promoted remarkably the induction of DH. The reactivity was enhanced considerably by w/o/w and to a less extent by aluminium. However, pertussis vaccine showed an adverse effect on DH by the fp route. Active cutaneous anaphylaxis (ACA) induced by the subcutaneous route was enhanced by w/o/w, endotoxin, pertussis vaccine and, to a less extent, by aluminium. The fp route com-pared with the sc route enhanced ACA by plain toxoid; w/o/w and aluminium but not endotoxin and the vaccine showed adjuvanticities. The influences of adjuvants and the route of injection on Arthus reactions were inconsistent. The effect of adjuvants on antitoxin production was quite different from that on DH when antitoxin was produced abundantly. Aluminium showed consistently a potent adjuvanticity, but the activities of w/o/w, endotoxin and pertussis vaccine were inconsistent 4-6 weeks after the primary stimulus by the subcutaneous route. The adjuvant effect became less significant in the secondary response. The fp route was more favorable for antitoxin production than the subcutaneous route with most adjuvants except pertussis vaccine added to tetanus toxoid. Antitoxin production by plain toxoid was very poor when administered intraperitoneally; aluminium and w/o/w but not endotoxin showed a remarkable adjuvanticity for the antitoxin production.
Article
In a previous paper we reported that an inbred strain of SL mice and an outbred strain of CF1 mice belonged to the high-responder strains in antibody production after primary immunization with hamster erythrocytes (H-RBC), while inbred strains of C57BL/6, AKR and C3H/He mice belonged to low-responder strains. In the present study we obtained the following results. 1) Pre-sensitization with hamster lymphoma enhanced antibody production after an intravenous injection of H-RBC. There was no strain difference in the pattern of antibody production against H-RBC among pre-sensitized mice. 2) The pattern of enhanced antibody production after an intravenous injection of H-RBC into pre-sensitized mice assumed the primary type in terms of time of appearance of hemolysin plaque-forming cells (PFC) in the spleens and the conversion from 2-mercaptoethanol sensitive to 2-mercaptoethanol resistant antibody production, when the intervals between both treatments were within 7 days. 3) Pre-sensitization with lymphoma induced not only an increase in numbers of PFC after an intravenous injection of H-RBC, but also an increase in the size of the hemolysin plaques. These results suggested that sensitization with hamster lymphoma stimulated some kinds of immuno-competent cells, which could contribute to antibody production against H-RBC after a booster injection of H-RBC.
Chapter
ResultsThe Tuberculin ReactionThe Reaction of Contact AllergyHomograft RejectionThe Experimental Auto-allergiesDelayed Allergy to Purified ProteinNon-specific Inflammatory ReactionsDiscussionSummaryReferencesDiscussion
Article
1. Intravenous injection of 0.03 mg of rabbit antibody-nitrogen will passively sensitize a guinea pig so that fatal anaphylaxis will result on injection of 1 mg of antigen in the egg-albumin system or 0.1 mg of specific polysaccharide in the type 3 pneumococcus system. 2. The anaphylactic response is dependent to a very great extent on the amount of antigen used. The best anaphylactic response occurs in the region of large antigen-excess. 3. The isolated guinea-pig uterus has about the same range of sensitivity as the intact animal, though it need contain amounts of antibody of the order of only 0.01 μg for contraction to be produced. 4. The relation of these findings to the in vitro methods of detecting antibody is discussed.
Article
The crystalline egg albumin and egg globulin differ considerably in their relationship to the different manifestations of hypersensitiveness. The crystalline egg albumin tends to sensitize the organism to those manifestations of the hypersensitiveness which are mediated by antibodies. The egg globulin tends to sensitize to those in which the active immunization plays the more important rôle. The difference between the antigens lies in their capacity to produce a different type of sensitization. We find no marked difference between them concerning their capacity to produce antibodies or to elicit the reactions themselves. The observations with crystalline egg albumin and egg globulins present an analogy to the behavior of certain bacterial antigens which we usually find connected either with the tuberculin or with the anaphylactic type of sensitiveness. We have given a short review of our experiences concerning the capacity of different antigens to produce the tuberculin type of skin sensitiveness. With all innocuous antigens which we tested—as eggwhite and animal sera—we succeeded in producing this sensitiveness. With bacterial antigens we have not so far succeeded in producing it.
Article
The following evidence is presented to show that tuberculin sensitivity passively induced in normal guinea pigs by means of peritoneal exudate cells from donors sensitized with BCG in Freund's adjuvants is not preceded by a latent period. In animals given cells intravenously and tested at the same time by the intradermal, intracorneal, or intraperitoneal injection of tuberculin, typical local or systemic reactions are produced. The same is true when cells and tuberculin are mixed and injected into the skin, or when cells are administered by the intraperitoneal route and the recipients are simultaneously tested by systemic tuberculin injection. Typical local reactions can also be induced by “reverse transfer”, i.e., by injecting cells intravenously into animals skin-tested 3 to 24 hours earlier. By contrast, cutaneous reactivity in guinea pigs which have received cells intraperitoneally is not established until about 20 hours after cell transfer. Minimal and maximal skin reactivity are induced, under the conditions of these experiments, by the intravenous injection of about 0.05 and 0.3 ml moist packed cells, respectively. In animals given equivalent amounts of cells intravenously, the reactions to multiple intradermal test doses of tuberculin are markedly weaker than the reaction to a single dose, a phenomenon that has been previously described by others in passively induced Arthus reactivity. In corroboration of the results reported by other workers, it has been observed that transferred tuberculin sensitivity does not last longer than a few days and that, after freezing or heating, cells lose their capacity for passive sensitization. The bearing of these findings on the possible mechanism of the tuberculin reaction is discussed, and it is suggested that the response of passively sensitized animals is brought about by a direct interaction between tuberculin and transferred cells.
Article
1. The relationships in passive anaphylaxis between the sensitizing dose of antibody, the shock dose of antigen and the severity of anaphylactic shock in the guinea pig have been investigated for the ovalbumin, tobacco mosaic virus, SIII and their homologous rabbit antibodies and for the cross reaction between SVIII and anti-SIII. 2. The sera of guinea pigs sensitized with varying quantities of antibody were assayed for circulating antibody by the micro quantitative precipitin method at the time when shock would usually be elicited. 3. The significance of differences in the quantitative relationships required for anaphylactic shock in the various antigen-antibody systems and the influence of circulating antibody on the severity of anaphylaxis is discussed.
Article
A method has been described by which sensitization to a simple chemical, picryl chloride (2:4:6 trinitrochlorobenzene), can be satisfactorily attained by means of intraperitoneal injection of the compound when killed tubercle bacilli suspended in paraffin oil were used as adjuvant. Sensitivity of the contact dermatitis type results therefrom. It follows that although skin sensitization of this type is most easily obtained by dermal application this route of administration is no necessary condition for such sensitivity.
Article
A general method for induction of the delayed hypersensitive state directed against single protein antigens is described. The method consists of intradermal injection of minute amounts of washed immune precipitates containing the antigen in question. Provided the specific precipitates are formed in the region of antibody excess, maximal sensitivity develops at least 2 to 3 weeks before detectable circulating antibody is formed in guinea pigs against the sensitizing antigen. Neither adjuvant nor killed acid-fast bacteria are required for induction of the delayed hypersensitive state although the degree of sensitization is considerably increased when the sensitizing material is incorporated in Freund's complete adjuvant. Characteristics of the "delayed" as opposed to the "immediate" hypersensitive states in the guinea pig are described and implications of the findings are discussed.
Article
Eight 2,4-dinitrophenyl compounds with a high degree of configurational uniformity were examined in regard to their ability to elicit delayed allergic skin reactions in guinea pigs and men who had been sensitized by previous exposure to 2,4-dinitrofluorobenzene. Four of the eight compounds produced reactions (elicitors) and four others did not (non-elicitors). It was found that the elicitors combined with protein in vitro and in vivo. The non-elicitors, however, failed to combine in either situation. It is concluded that a necessary condition for the elicitation of delayed allergic skin reactions by haptens is the combination of the latter with skin protein through the formation of bonds of the covalent type. No choice is yet possible amongst the several possible explanations which are advanced to account for the obligatory character of protein combination.
Article
1. The effects of acid and alkali on several purified plasma proteins employed as antigens, and on their homologous specific precipitates, have been reported. The ultraviolet absorption properties of these antigens and their homologous rabbit antibodies have been shown to be largely dependent upon their tyrosine and tryptophane content. 2. The ultraviolet absorption properties of the rabbit antibodies studied are very similar to those of human serum γ-globulin, and it is suggested that the tyrosine and tryptophane content of the rabbit antibodies is very similar to that of human serum γ-globulin. 3. E1%1cm has been calculated for several rabbit antibodies. 4. A method is described for using the spectrophotometer for studies of the quantitative precipitin reaction. 5. The spectrophotometric method of determining total and antibody protein in specific precipitates has been applied to the study of the precipitation of several human and bovine plasma proteins by their homologous rabbit antisera.
Article
1. It has been possible to passively transfer in 12 consecutive instances cutaneous tuberculin hypersensitivity to tuberculin negative human recipients by means of an intradermal injection of viable leucocytes obtained from the blood of tuberculin positive human donors.
The technic of a method for quantitative determination of diphtheria antitoxin by a skin test in rabbits, Tr
  • D T Fraser
Fraser, D. T., The technic of a method for quantitative determination of diphtheria antitoxin by a skin test in rabbits, Tr. Roy. Soc. Canada, Section V, 1931, 9.5, 175.