Editorial overview: Immunomodulation: Exploiting the circle between emotions and immunity: impact on pharmacological treatments

Abstract

ociety is rapidly changing and so are many aspects of our daily living. From the ways we
communicate with each other to the goods we consume, the most striking change we have
witnessed in the last decades is the falling of barriers between apparently diverse parts of
society and the merging of different cultures and points of view. We have called this
phenomenon ‘globalization’ and, according to its definition, this is “the process by which the
world is becoming increasingly interconnected as a result of massively increased trade and
cultural exchange”. How does globalization manifest in science and scientific research? The
short answer is ‘system biology’ e.g. the understanding and analysis of biological phenomena
through the lenses of different and yet complementary disciplines (mathematics combined
with enzymology for instance)[1].
Translating these concepts into the world of pharmacology and drug discovery, one could say
diseases are not just a straight line - one organ/one cell/one signalling pathway - but rather a
spider diagram where different ‘factors and problems’ all converge to a single point. With
this in mind, it would be tempting to say that the benefits of combining different approaches
to achieve an improved and safer pharmacological therapy should be a no brainer. In this
section of Immunomodulation, we have been inspired by this concept and have explored the
link between mind and body in general - the interconnectedness between emotional states and
the immune system specifically - as a possible venue for an improved treatment of both
immune and emotional disorders. I have named this area of research Affective Immunology
(http://www.affectiveimmunology.com).

Full text

COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments
Fulvio
D’Acquisto
Current
Opinion
in
Pharmacology
2016,
29:xx–yy
http://dx.doi.org/10.1016/j.coph.2016.07.008
1471-4892/Crown
Copyright
#
2016
Published
by
Elsevier
Ltd.
All
rights
reserved.
Society
is
rapidly
changing
and
so
are
many
aspects
of
our
daily
living.
From
the
ways
we
communicate
with
each
other
to
the
goods
we
consume,
the
most
striking
change
we
have
witnessed
in
the
last
decades
is
the
falling
of
barriers
between
apparently
diverse
parts
of
society
and
the
merging
of
different
cultures
and
points
of
view.
We
have
called
this
phenomenon
‘globalization’
and,
according
to
its
definition,
this
is
‘the
process
by
which
the
world
is
becoming
increasingly
interconnected
as
a
result
of
massively
increased
trade
and
cultural
exchange’.
How
does
globalization
manifest
in
science
and
scientific
research?
The
short
answer
is
‘system
biology’
for
example
the
understanding
and
analysis
of
biological
phenomena
through
the
lenses
of
different
and
yet
complementary
disciplines
(mathematics
combined
with
enzymology
for
instance)
[1].
Translating
these
concepts
into
the
world
of
pharmacology
and
drug
discovery,
one
could
say
diseases
are
not
just
a
straight
line
—
one
organ/
one
cell/one
signalling
pathway
—
but
rather
a
spider
diagram
where
dif-
ferent
‘factors
and
problems’
all
converge
to
a
single
point.
With
this
in
mind,
it
would
be
tempting
to
say
that
the
benefits
of
combining
different
approaches
to
achieve
an
improved
and
safer
pharmacological
therapy
should
be
a
no
brainer.
In
this
section
of
Immunomodulation,
we
have
been
inspired
by
this
concept
and
have
explored
the
link
between
mind
and
body
in
general
—
the
interconnectedness
between
emotional
states
and
the
immune
system
specifically
—
as
a
possible
venue
for
an
improved
treatment
of
both
immune
and
emotional
disorders.
I
have
named
this
area
of
research
Affective
Immunology
(http://www.affectiveimmunology.com).
Why
would
the
link
between
emotions
and
immunity
be
important
for
drug
design?
And
why
should
pharmacologists,
in
particular,
be
investigating
this
area
of
research?
The
answers
to
these
questions
are
multiple.
First,
some
immunomodulatory
therapies
present
serious
emotional
side
effects
(in-
creased
suicide
idealization)
[2,3],
and
others
might
provide
a
better
thera-
peutic
effect
when
administered
with
‘emotional
modulators’
(see
later)
[4].
Second,
pharmacological
therapies
for
mood
disorders
have
been
shown
to
be
more
effective
when
co-administered
with
immunomodulatory
drugs
in
specific
cohorts
of
patients
[5–7].
What
are
the
cellular
and
molecular
mechanisms
underlying
the
connection
between
emotions
and
immunity?
We
know
first
of
all
that
the
immune
system
plays
a
key
role
in
maintaining
the
emotional
system
under
check
[8–10].
Studies
in
both
experimental
animals
and
humans
have
shown
that
a
Fulvio
D’Acquisto
William
Harvey
Research
Institute,
Queen
Mary
University
of
London,
Barts
and
the
London
School
of
Medicine
and
Dentistry,
Queen
Mary
University
of
London,
London,
UK
e-mail:
F.Dacquisto@qmul.ac.uk
Fulvio
D’Acquisto
is
a
professor
of
Immunopharmacology
at
the
William
Harvey
Research
Institute,
Queen
Mary
University
of
London
in
UK.
His
current
field
of
research
(called
Affective
Immunology;
http://www.
affectiveimmunology.com)
investigates
the
cross-talk
between
emotions
and
the
immune
system
as
a
new
venue
for
the
treatment
of
autoimmune
and
inflammatory
disorders.
Available
online
at
www.sciencedirect.com
ScienceDirect
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:1–5

dysfunctional
or
absent
immune
system
causes
some
emotional
disorders
including
anxiety,
depression,
obses-
sive-compulsive
disorders
and
increased
risk
of
suicide
[11–13].
In
mice,
the
absence
of
immune
cells
causes
significant
changes
in
memory
and
cognition
[14–16]
and
increases
the
animal’s
constitutive
basal
level
of
anxiety-
like
behavior
[17,18].
These
effects
are
linked
to
some
mechanisms
including
the
lack
of
homeostatic
‘patrolling’
exerted
by
the
immune
cells
into
the
CNS
through
newly
discovered
lymphatic
vessels
[19,20].
Studies
also
suggest
that
the
absence
of
T
cells
causes
specific
changes
in
the
gene
expression
profile
of
the
whole
brain,
and
these
have
been
associated
with
both
anxiety
disorders
and
neuro-
degenerative
diseases
[17].
Similar
findings
have
been
reported
in
humans
as
patients
with
either
a
deficient
immune
system
(HIV)
[21,22]
or
those
with
a
hyper
activated
one
(autoimmune
diseases)
are
known
to
pres-
ent
a
high
incidence
of
emotional
disorders
[23–26].
Despite
this
evidence,
the
scientific
community
seems
to
be
reluctant
to
appreciate
the
therapeutic
value
of
these
observations.
As
Lasselin
and
colleagues
stated
in
their
article,
most
people
are
still
surprised
to
hear
that
‘immu-
nity
is
tuned
by
one’s
emotions,
personality
and
social
status’.
Therefore,
it
might
come
not
as
a
surprise
to
know
that
a
defective
immune
response
could
be
treated
by
com-
bined
targeting
of
the
emotional
and
immunological
systems.
As
the
authors
suggested,
this
‘resistance’
might
be
because
emotional
wellbeing
is
not
well-defined
and
hence
difficult
to
quantify.
The
absence
of
‘universal’
and
well-tested
animal
models
for
the
study
of
emotional
wellbeing
might
be
another
cause.
Besides
these
consid-
erations,
I
think
that
the
resistance
also
lays
on
the
fact
that
wellbeing
is
not
just
about
how
we
feel
but
also
about
how
we
are,
as
suggested
by
the
authors
and
others
[27].
This
is
rather
important
as
it
suggests
that
therapies
tackling
‘how
one
is’
or
in
other
terms
one’s
life
style
might
be
potentially
useful
when
combined
with
standard
immunomodulatory
therapies.
Along
these
lines,
a
large
body
of
evidence
has
shown
a
direct
correlation
between
life
style,
oxidative
stress
and
immune
and
inflammatory
chronic
diseases
[28–30].
The
article
by
Samina
Salin
discusses
the
role
of
oxidative
stress
in
neuroinflammation
and
the
fact
that
many
psychiatric
illnesses
are
reported
to
exhibit
low
plasma
concentrations
of
a
variety
of
antioxidants
including
glutathione,
vitamin
E
and
coenzyme
Q10.
The
idea
that
the
combined
administration
of
immunomodulators
and
changes
in
life-style
might
be
beneficial
for
the
therapy
of
immune
and
emotional
dis-
orders
is
indeed
fascinating
as
Chiurchiu
and
Maccarone
suggested.
In
their
article,
the
authors
focused
their
atten-
tion
on
bioactive
lipids
[31–33]
and
their
dual
role
in
immunity
and
emotions.
From
classical
lipids
like
eicosa-
noids
and
phospholipids
to
more
recent
new
entries
such
as
specialized
pro-resolving
lipid
mediators,
the
range
of
med-
iators
that
could
be
pharmacologically
exploited
for
their
dual
pharmacological
effects
on
emotional
state
[34,35]
and
immunity
[36,37]
seems
to
be
growing
by
the
year.
Of
a
particular
note
for
the
topic
of
this
volume,
the
endocanna-
binoid
anandamide
is
the
prototype
of
lipid
mediator
that
has
remarkable
effects
on
the
immune
system
[38]
and
is
equally
effective
in
emotional
disorders
[39,40]
as
its
name
(which
means
‘inner
bliss’)
seems
to
suggest.
The
idea
of
drugs
with
a
potential
double
role
in
the
immune
and
emotional
systems
is
not
entirely
new.
Neigh
and
Ali
have
provided
an
interesting
overview
of
immunomodulatory
drugs
—
from
the
classical
steroid
to
the
modern
biologic
against
inflammatory
cytokines
—
that
are
proven
for
the
treatment
of
post-traumatic
stress
disorders
(PTSD).
The
authors
also
highlighted
that
several
drugs
used
for
the
treatment
of
PTSD,
including
selective
serotonin
re-uptake
inhibitors
(SSRI),
have
been
shown
to
exert
anti-inflammatory
effects
on
T-lymphocytes,
dendritic
cells,
and
neutrophils.
This
simultaneous
effect
on
both
the
immune
and
emo-
tional
system
can
also
be
achieved
by
co-therapy.
In
their
article
Rosenblat
and
co-authors
describe
the
efficacy
of
co-therapy
in
the
treatment
of
patients
suffering
from
bipolar
disorders.
Similar
to
what
has
been
found
for
PTSD
or
depression,
a
wide
range
of
drugs
including
N-
acetylcysteine,
infliximab,
pioglitazone,
celecoxib,
aspirin,
and
omega-3
polyunsaturated
fatty
acids
have
shown
an
antide-
pressant
effect
in
bipolar
disorders
when
administered
adjunc-
tively
to
conventional
treatments.
Co-therapies
have
also
been
particularly
useful
in
the
context
of
immunomodulatory
treatment.
Indeed,
Kovacs
and
co-authors
provided
an
extensive
overview
of
the
side
effects
on
the
emotional
system
of
a
powerful
antiviral
and
anticancer
drug:
interferon-alpha
[41].
As
stated
by
the
authors,
a
staggering
10%–40%
of
patients
receiving
this
therapy
develop
a
full
depressive
disorder
syndrome
that
can
include
suicidal
ideation,
aboulia,
lack
of
motiva-
tion,
social
withdrawal,
guilt,
anhedonia,
irritability,
anxiety,
and
crying
[42,43].
Luckily,
the
side
effects
of
this
drug
seem
to
be
tapered
by
the
co-treatment
with
traditional
drugs
such
as
SSRI
[44]
or
novel
ones
such
as
a
diet
rich
in
omega-3
polyunsaturated
fatty
acids
[45].
Is
there
any
other
approach
to
co-therapies?
As
we
have
just
started
to
better
appreciate
the
colloquium
between
the
brain
and
immune
cells,
an
extra
level
of
control
has
been
taking
the
center
stage
in
the
scientific
arena:
the
gut–brain
axis
or
—
to
be
more
precise
—
the
gut–brain–
immune
system
triangle.
The
colloquium
has
now
been
transformed
into
colloquia.
The
discoveries
emerging
from
this
field
of
research
are
bewildering,
to
say
the
least
[46–48].
As
Hayley
and
colleagues
pointed
out,
bacterial
communities
generally
present
in
the
gut
are
sensitive
to
a
variety
of
challenges,
including
stressors
—
the
stressors
being
of
emotional
nature
(the
most
famous
2
Immunomodulation
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Current
Opinion
in
Pharmacology
2016,
29:1–5
www.sciencedirect.com

‘gut
feelings’)
or
a
pathogenic
factor
for
the
immune
system.
In
their
view,
the
gut
is
the
real
link
between
the
brain
and
the
immune
system
as
evidenced
by
the
fact
that
the
benefits
of
microbiota-targeting
compounds
on
mood
states
could
be
related
to
their
actions
on
immune
processes.
Prebiotics
and
pro-biotics
are
the
new
classes
of
drugs
currently
under
investigation
for
their
use
in
immune
and
psychiatric
disorders
[49–51].
Where
do
we
move
from
here?
Figure
1
shows
a
tag
cloud
analysis
of
the
most
common
terms
present
in
all
the
contributions
to
this
volume
and
highlight
the
’chal-
lenges’
ahead
of
us.
From
my
personal
perspective,
there
are
still
two
most
important
aspects
that
need
to
be
explored.
First,
the
role
of
emotions
and
immune
cells
as
guardian
of
wellbeing.
As
Ruslan
Medzhitov
has
highlighted
in
his
recent
reviews
[52,53],
the
state
of
homoeostasis
of
the
immune
system
cannot
be
just
inter-
preted
as
absence
of
threats
from
the
external
environ-
ment.
Emotions
like
stress
or
simply
having
a
laugh
are
part
of
daily
living,
and
as
Steve
Cole
and
colleagues
has
very
elegantly
shown,
they
directly
steer
the
immune
system
towards
specific
tasks
such
as
antibacterial
de-
fense
pathway
or
antiviral
response
depending
on
social
factors
such
as
isolation
[54–56].
Unraveling
the
molecu-
lar
mechanisms
regulating
these
events
might
provide
an
immense
resource
for
pharmacologists
to
identify
new
molecules
and
drugs
that
can
help
maintain
the
host
in
a
state
of
immunological
equilibrium
and
possibly
a
healthy
emotional
state.
The
other
aspect
that
has
not
been
thoroughly
investi-
gated
is
the
contribution
of
emotional
or
immunological
systems
in
controlling
the
transition
between
acute
and
chronic
diseases.
Indeed,
it
could
be
that
the
disturbance
in
emotional
wellbeing
is
one
of
the
leading
causes
that
make
acute
inflammatory
response
transform
into
chronic
autoimmune
disorders.
Similarly,
change
in
the
immune
system
might
constitute
the
tipping
point
for
a
weak
emotional
state
to
become
a
chronic
and
morbid
mood
condition.
The
validation
of
this
hypothesis
would
lead
to
an
entirely
new
therapeutic
protocol
where
co-therapy
will
be
substituted
by
sequential
therapies.
Thus,
a
patient
with
high
risk
of
mental
disorders
will
be
given
treatment
for
the
mental
disorder
first
and
an
immuno-
modulatory
therapy
as
a
preventative
of
future
flares.
Similarly,
patients
with
autoimmune
diseases
will
be
treated
with
immunosuppressants
during
the
acute
phase
of
the
disease
and
then
kept
under
‘emotional
modula-
tors’
as
soon
as
remission
comes
up.
Clearly,
the
validity
of
such
protocols
will
require
several
clinical
trials
before
a
definite
answer
can
be
reached.
In
the
meantime,
I
hope
that
this
volume
on
immunomo-
dulation
will
convince
my
pharmacologist
colleagues
as
well
as
scientists
from
other
disciplines
to
‘open
their
mind’
and
wonder
if
the
disease
they
are
studying
could
also
be
looked
at
from
the
perspective
of
an
apparently
distant
area
of
research.
As
history
and
current
events
have
convincingly
shown
‘separation’
is
never
the
best
and
most
convenient
choice
to
address
a
problem.
In
life
as
in
science!
Conflict
of
interest
statement
Nothing
.declared.
Acknowledgements
I
am
very
grateful
to
Dr
Dianne
Cooper
and
Dr
Lucy
Norling
for
their
feedback
and
suggestions.
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MW:
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75:975-977.
Editorial
overview
D’Acquisto
3
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Figure
1
Current Opinion in Pharmacology
Affective
Immunology:
where
immunity
and
emotions
converge.
Tag-cloud
analysis
of
the
most
common
terms
used
in
the
contributions
made
to
this
volume
of
Current
Opinion
in
Pharmacology
dedicated
to
Immunomodulation.
Terms
like
‘‘depression’’,
‘‘PTSD’’,
‘‘inflammation’’,
‘‘stress’’
and
‘‘cytokines’’
had
the
highest
score
(cited
more
than
70
times)
and
might
represent
the
common
feature
among
all
the
topics
that
have
been
explored.
Terms
like
‘‘microglia’’,
‘‘GSH’’
and
‘‘gut’’
were
the
least
used
(cited
10
times)
and
might
represent
themes
that
are
developing
or
are
more
relevant
to
specific
aspects.
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:1–5

6.
Ghanizadeh
A,
Hedayati
A:
Augmentation
of
citalopram
with
aspirin
for
treating
major
depressive
disorder,
a
double
blind
randomized
placebo
controlled
clinical
trial.
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Antiallergy
Agents
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Chem
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KS,
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HY:
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of
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9.
D’Acquisto
F,
Rattazzi
L,
Piras
G:
Smile
—
it’s
in
your
blood!
Biochem
Pharmacol
2014,
91:287-292.
10.
Brod
S,
Rattazzi
L,
Piras
G,
D’Acquisto
F:
‘As
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so
below’
examining
the
interplay
between
emotion
and
the
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2014,
143:311-318.
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GA,
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CL:
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cognition
and
emotion:
is
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2011,
25:591-601.
12.
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CJ,
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Stress
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autoimmunity.
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L:
Stress
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2010,
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J,
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S,
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JT,
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J:
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Schwartz
M,
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the
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immunity.
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2011,
25:817-819.
17.
Rattazzi
L,
Piras
G,
Ono
M,
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R,
Pariante
CM,
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F:
CD4(+)
but
not
CD8(+)
T
cells
revert
the
impaired
emotional
behavior
of
immunocompromised
RAG-1-deficient
mice.
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D,
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UC:
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stress
and
metabolic
disorders:
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2016,
148:183-193.
29.
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I,
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L,
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JA:
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stress
and
inflammation
interactions
in
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2012,
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30.
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M,
Sahraei
Z,
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J,
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S,
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ND:
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stress
in
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causes,
consequences,
and
potential
treatment.
Iran
J
Kidney
Dis
2011,
5:357-372.
31.
Nadjar
A,
Leyrolle
Q,
Joffre
C,
Laye
S:
Bioactive
lipids
as
new
class
of
microglial
modulators:
when
nutrition
meets
neuroimunology.
Prog
Neuropsychopharmacol
Biol
Psychiatry
2016.
32.
Tintut
Y,
Demer
LL:
Effects
of
bioactive
lipids
and
lipoproteins
on
bone.
Trends
Endocrinol
Metab
2014,
25:53-59.
33.
Nagao
K,
Yanagita
T:
Bioactive
lipids
in
metabolic
syndrome.
Prog
Lipid
Res
2008,
47:127-146.
34.
Berger
GE,
Smesny
S,
Amminger
GP:
Bioactive
lipids
in
schizophrenia.
Int
Rev
Psychiatry
2006,
18:85-98.
35.
Condray
R,
Yao
JK:
Cognition,
dopamine
and
bioactive
lipids
in
schizophrenia.
Front
Biosci
(Schol
Ed)
2011,
3:298-330.
36.
Cabral
GA,
Ferreira
GA,
Jamerson
MJ:
Endocannabinoids
and
the
immune
system
in
health
and
disease.
Handb
Exp
Pharmacol
2015,
231:185-211.
37.
Dennis
EA,
Norris
PC:
Eicosanoid
storm
in
infection
and
inflammation.
Nat
Rev
Immunol
2015,
15:511-523.
38.
Maccarrone
M,
Bab
I,
Biro
T,
Cabral
GA,
Dey
SK,
Di
Marzo
V,
Konje
JC,
Kunos
G,
Mechoulam
R,
Pacher
P
et
al.:
Endocannabinoid
signaling
at
the
periphery:
50
years
after
THC.
Trends
Pharmacol
Sci
2015,
36:277-296.
39.
Ashton
CH,
Moore
PB:
Endocannabinoid
system
dysfunction
in
mood
and
related
disorders.
Acta
Psychiatr
Scand
2011,
124:250-261.
40.
Moreira
FA,
Wotjak
CT:
Cannabinoids
and
anxiety.
Curr
Top
Behav
Neurosci
2010,
2:429-450.
41.
Arico
E,
Belardelli
F:
Interferon-alpha
as
antiviral
and
antitumor
vaccine
adjuvants:
mechanisms
of
action
and
response
signature.
J
Interferon
Cytokine
Res
2012,
32:235-247.
42.
Raison
CL,
Demetrashvili
M,
Capuron
L,
Miller
AH:
Neuropsychiatric
adverse
effects
of
interferon-alpha:
recognition
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management.
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19:105-123.
43.
Schaefer
M,
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MA,
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a
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KP,
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Y,
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CU:
Omega-3
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in
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of
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and
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4
Immunomodulation
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Current
Opinion
in
Pharmacology
2016,
29:1–5
www.sciencedirect.com

51.
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Editorial
overview
D’Acquisto
5
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:1–5