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Annu.Rev. Psychol.1993. 44:53~5
Copyright 1993by AnnualReviewsnc. All rights reserved
PSYCHONEUROIMMUNOLOGY:
CONDITIONINGAND STRESS
Robert Ader and Nicholas Cohen
Departmentf Psychiatry and Microbiologynd Immunology,niversityof Rochester
Schoolof Medicine nd Dentistry, Rochester, NewYork14642
KEYWORDS:sychoneuroimmunology, conditioning, stress
CONTENTS
INTRODUCTION.................................................................................................................... 53
CONDITIONEDODULATIONF MMUNITY............................................................... 54
Effectsof ConditioningnHumoralndCell-Mediatedmmunity.................... 55
Effectsof ConditioningnNonimmunologicallypecificReactions.................
59
AntigensUnconditionedtimulus....................................................................
60
Biologicmpactf Conditionedhangesn Immunity.......................................
61
Conditioningn Humanubjects........................................................................ 61
STRESSNDMMUNITY.....................................................................................................63
Effectsf StressnDisease.................................................................................
64
Effectsof StressonHumoralndCell-Mediatedmmunity...............................
66
Effects f StressonNonimmunologicallypecificReactions.............................
69
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54 ADER & COHEN
ity and, conversely, the immune tatus of an organism has consequencesfor
behavior. This new research indicates that the nervous and immune ystems,
the two most complex systems involved in the maintenance of homeostasis,
represent an integrated mechanismontributing to the adaptation of the indi-
vidual and the species. Psychoneuroimmunologymphasizes the functional
significance of the relationship between hese systems--not n place of, but in
addition to the more raditional disciplinary analysis of the mechanisms ov-
erning functions within a single system.
The range of phenomenahat bears on the relationship between behavior
and immunity s quite broad, and no attempt will be made o provide even a
cursory summaryf all this literature. We ocus here on animal studies of the
effects of conditioning and stress in the modulationof immuneunction. There
are several more or less programmatic ines of research in humans hat the
reader maywish to explore. These deal with the immunologic orrelates of
emotional states (primarily depression), personality traits as modulators
immune unction, and the effects of stress on immuneunction. Fewgeneral-
izations are possible based on currently available data. Although here is no
definitive evidence for the implied chain of events, the hypothesis that im-
mune unction maymediate the effects of psychosocial factors on the suscepti-
bility to or progression of somedisease processes remains tenable. We onfine
this review, however, to the experimental literature on the modulation of
immunity by stress and conditioning. Other recent reviews (e.g.S. Cohen
Williamson 1991; Geiser 1989; Kemeny t al 1992; OLeary 1990) have dealt
with personality and emotional factors and immunity nd/or disease. Someof
these have included an introductory outline of the immune ystem; an exten-
sive treatment of immuneunction can be found in any of several recent texts
(e.g. Stites & Ten"1991).
CONDITIONED MODULATIONOF IMMUNITY
Immuneesponses, like other physiological processes, can be modified by
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PSYCHONEUROIMMUNOLOGY5
little more han preliminary observations. Although he data on specific anti-
bodyresponses were not convincing, he studies of nonspecific cellular events
(e.g. changes in leukocyte number, phagocytosis, inflammatory responses)
were consistent and provided provocative evidence that conditioning could
modulatehost defenses. A detailed review (and some eanalyses) of these data
was provided by Ader (1981 b).
Effects of Conditioning on Humoral and Cell-Mediated
Immunity
Oneof the hallmarks of the immuneystems defense of the organismagainst
foreign, "nonself"material (antigens) is its specificity--its ability to recognize
precisely and then eliminate only the antigens it has confronted. These activi-
ties are carried out by a variety of white blood cells (leukocytes). Prominent
amonghese are T and B lymphocytes hat are capable of clonal proliferation
in response to antigens and retaining the "memory" f that encounter. Hu-
moral or antibody-mediated immunity nvolves the exposure of antigens to
bone marrow-derivedB cells. These cells effect the ultimate production of
antibodies that protect the organismagainst extracellular microorganisms nd
reinfection. Cell-mediated immunity s provided by thymus-derived T cells
that protect against intracellular parasitic and viral infections. An ntegrated
immuneesponse to antigens, however, involves complex nteractions among
specialized subpopulationsof T cells (i.e. helper, suppressor, cytotoxic),
cells, other white blood cells such as macrophages, nd substances (cytokines)
that are secreted by activated leukocytes. A variety of techniques have been
developed o measure hese cellular interactions in vitro. The essence of psy-
choneuroimmunology,owever, s the recognition that in vivo these reactions
occur within a neuroendocrinemilieu that is demonstrably sensitive to the
organisms perception of and adaptation to events occurring in its environ-
ment.
HUMORALMMUNITYurrent interest in conditioned changes in immunologic
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56 ADER & COHEN
animals received saccharin. A placebo-treated group was injected with vehicle
after consuming accharin or water before immunization and was exposed to
saccharin after immunization. As expected, conditioned animals showed an
aversion to the saccharin solution that had been paired with CY.Conditioned
animals that were eexposed o the CSat the time of, and/or three days after,
immunizationalso showed n attenuated anti-SRBC ntibody response relative
either to conditioned animals that were not reexposed to saccharin or to
nonconditioned nimals that were similarly exposed o saccharin. These results
were interpreted as reflecting a conditioned immunosuppressiveesponse. The
acquisition and the experimentalextinction of a conditionedsuppression and/or
enhancement of antibody- and cell-mediated immune esponses as well as
nonspecific host defenses have nowbeen observed under a variety of experi-
mentalconditions. Onlya brief overview f this research is providedhere; more
detailedreviews are available elsewhere (Ader & Cohen1985, 1991).
In the conditioned taste aversion paradigm,animals learn to avoid flavored
solutions previously paired with the noxious or illness-inducing effects of a
variety of (pharmacologic)agents; that is, they reduce their consumption
the CSsolution. Therefore, to obviate the conflict ("stress") inducedby having
either to drink a solution paired with illness or to remain thirsty--and to
equate total fluid consumptionamongdifferentially treated animals~ondi-
tioning can be assessed with a two-bottle preference procedure hat permits the
animal to choose between plain water and the flavored CS solution. Under
these conditions, conditioned alterations of humoral(e.g. Ader et al 1982;
Bovbjerget al 1987b; N. Cohenet al 1979) and cell-mediated (Bovbjerg et
1982, 1984) immune esponses are still obtained. The available literature
reveals no consistent relationship betweenconditioned behavioral (aversive)
responses and conditioned immune hanges in the taste aversion learning
paradigm; taste aversions can be expressed without concomitant changes in
humoral immunity, and conditioned changes in immune unction can be ob-
tained without observable conditioned avoidance responses (Ader & Cohen
1975; Ader et al 1987; Bovbjerget al 1987b; Gorczynski1987; Gorczynskiet
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PSYCHONEUROIMMUNOLOGY7
tained using electric shock as the UCS Sato et al 1984; Zalcman t al 1989,
1991b).
There have been a few studies in which there were no observable condi-
tioned effects (Krank & MacQueen 988; MacQueen& Siegel 1989). For
theoretical reasons (see Eikelboom& Stewart 1982), these experiments were
conducted with the expectation of observing "paradoxical" or compensatory
conditioned responses (responses opposite in direction to the unconditioned
response). In conditioned animals reexposed to a CS previously paired with
CY, he anti-SRBC ntibody response was higher than the response of condi-
tioned animals that were not reexposed to the CS and the response of animals
that experienced unpaired CS-UCSresentations, but the responses of condi-
tioned animalsreexposed o the CSdid not differ from hose of a saline-treated
control group. Suchresults maypermit one to infer the existence of a condi-
tioned enhancementof antibody production based on the failure to observe
immunosuppression,ut, as the investigators acknowledge, o direct evidence
of compensatoryconditioning was obtained. There is no obvious explanation
for the difference betweenhese results and those in the rest of the literature on
conditioned immunologic hanges.
Evidencefor the existence of the compensatoryconditioning of host de-
fense reactions, however,can be derived fromstudies on the role of condition-
ing in the development f pharmacological olerance to repeated injections of
polyinosinic-polycytidylic acid (poly I:C; Dyck t al 1986, 1987). In keeping
with a conditioning analysis of the developmentof tolerance to someother
pharmacologicgents (Siegel 1983), tolerance to the enhancingeffects of poly
I:C on natural killer cell activity is abrogatedby unreinforcedexposures o the
CS; preexposure to the CS nterferes with the developmentof tolerance; and
tolerance is attenuated when oly I:C is injected in the absence of environmen-
tal cues previouslypaired with injections of the drug.
CELL-MEDIATEDMMUNITYhe immunosuppressiveeffects of CYcan also be
used to condition changes n cell-mediated esponses. In the studies by Bovbjerg
et al (1982, 1984), (Lewis x BrownNorwegian)Flats were injected with Lewis
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58 ADER&COHEN
from Lewis strain donors. On the day of grafting and on the following two days
they were reexposed to the CS; on the day after grafting they were also given a
low dose injection of CY. While low-dose injections of CY on Days 0, 1, and
2 dramatically suppressed the local GvH esponse, a single injection on Day l
caused only a modest decrease in the response. However, a single low-dose
injection of CYplus reexposure to the CS previously paired with CYsignifi-
cantly suppressed the GvH esponse relative to control groups that received only
the single low-dose injection of CY. As expected, unreinforced exposures to the
CS during the 7-week interval between conditioning and induction of the GvH
response resulted in extinction of the conditioned immunosuppressiveresponse.
Experimental extinction, one hallmark of a conditioned response, has also been
reported for other conditioned immunologic effects (Dyck et al 1986;
Gorczynski et al 1982; see also Lysle et al 1988).
Cyclophosphamide can enhance as well as suppress immunologic reactiv-
ity. In the case of a delayed-type hypersensitivity (DTH)
reaction to SRBC,
low-dose treatment with CY at the time of sensitization can enhance DTH n
response to a subsequent challenge with the same antigen (Turk & Parker
1982); CY reatment of sensitized animals just before antigenic challenge
decreases the DTH esponse (Gill & Liew 1978; Rodinone et al 1983). Al-
though CY decreases the DTbI reaction to an initial antigenic challenge, the
response to subsequent challenges is enhanced (Bovbjerg et al 1986).
Bovbjerg et al (1987a) did not observe any conditioning effects when sensi-
tized animals, previously conditioned with CY, were reexposed to the CS
before their initial challenge. However, reexposing conditioned animals to the
CS before two subsequent antigenic challenges resulted in enhanced DTH
responses. The conditioned enhancement could be a consequence of a selec-
tive conditioned immunosuppressive effect on suppressor cells (Gill & Liew
1978; Mitsuoka et al 1979). Another drug, levamisole, has been purported to
selectively depress cytotoxic/suppressor T cells. Thus, the conditioned eleva-
tion of the T-helper:T-suppressor-subset ratio in animals reexposed to a CS
previously paired with levamisole (Husband et al 1987) could be the phenom-
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PSYCHONEUROIMMUNOLOGY9
males) were reexposed to the CS on Days 13, 16, and 19 of gestation, there
was a depression of humoral and cell-mediated immunity in their un-
manipulatedoffspring.
Effects of Conditioning on Nonimmunologically Specific
Reactions
In addition to studying antibody- and cell-mediated immunity, mmunologists
also study the nonimmunologicallypecific in vitro actions of natural killer
cells and mitogens. These are among he most frequently used measures in
behavioral experiments. Natural killer (NK)cells are large granular lympho-
cytes that nonspecifically attack and destroy certain virus-infected cells and
tumor cells and maybe involved in preventing tumor metastasis.
T and/or B lymphocytes an be induced to proliferate in vitro by stimula-
tion with various lectins (chemical substances obtained from plants), and the
lymphoproliferative response to such mitogens has been used to indicate an
alteration of the physiological state of T or B cells in a particular lymphoid
compartment e.g. spleen, lymphnodes, peripheral blood). Changes n mitt-
genie responsiveness, however,do not necessarily reflect an organismsabil-
ity to respond to antigens in vivo or in an immunologicallypecific manner.
In a comprehensive eries of experiments, Lysle and his colleagues (1988,
1990a,b, 1991, 1992b)characterized the conditioned suppression of a variety
of nonspecific responses in rats rcexposcd to cues previously paired with
stressful stimulation. Comparedo nonconditioned animals, to conditioned
animals exposed to novel environmental cues, and to animals exposed to cues
explicitly unpaired with the UCS, nimals reexposed to auditory (or visual)
cues paired with electric shock stimulation showed reliable suppression of
lymphoproliferative responses to concanavalin A (Con A) and phytohemag-
glutinin (PHA) two T cell mitogens), lipopolysaccharide (LPS) (a
mitogen), interleukin-2 (IL-2)
3
production, and NK ell activity. As expected,
exposure to the CSbefore conditioning retarded developmentof the condi-
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60
ADER& COHEN
cells obtained from mesenteric lymphnodes showedno effects of CSreexpos-
ure.
Using either a taste or odor aversion conditioning paradigmor a stressor as
the UCS,other studies have also observed the conditioned suppression of
lymphoproliferative responses both to mitogenic stimulation. (Drugan et al
1986; Kusnecov et al 1988; Neveu et al 1986, 1987), NKcell activity
(Gorczynski et al 1984; Hiramoto et al 1987; Lysle & Maslonek 1991;
OReilly & Exon 1986), and total white blood cell count (Klosterhalfen
Klosterhalfen 1987). The conditioned enhancementof NKcell activity has
also been reported (Hiramotoet al 1987; Solvasonet al 1988, 1991). However,
someof these latter studies suffer from major design flaws, and others have
been unable to repeat these observations (Ader & Cohen 991):
In a recent study, Coussonset al (1992) paired exposure to a distinctive
environmental setting with injections of morphine (which unconditionally
suppresses several nonspecific immune esponses). Reexposure o the envi-
ronmentalcues resulted in a conditioned suppression of splenic and peripheral
blood lymphocyte esponse to T and B cell mitogens, splenic NK ell activity,
and IL-2 production. These esults are of additional interest in relation to the
issue of compensatory conditioning discussed above. The conditioned re-
sponse mimicked he unconditioned response rather than inducing an opposite
or compensatory esponse; induction of such a compensatoryresponse, how-
ever, characterizes someof the other behavioral and physiological effects of
morphine e.g. Siegel 1976, 1983).
As is the case with antibody-mediated esponses, the above studies uncov-
ered no consistent relationship betweenconditioned behavioral responses and
conditioned changes in nonspecific defense reactions (Klosterhalfen
Klosterhalfen 1987; Kusnecov t al 1988; Neveuet al 1986, 1987; Solvason et
al 1988).
Antigen as Unconditioned Stimulus
In behavioral terms, an antigen is an unconditioned timulus for activation of
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PSYCHONEUROIMMUNOLOGY1
conditioned immune responses as distinct from conditioned im-
munopharmacologicffects.
Biologic Impact of Conditioned Changes in Immunity
Althoughhighly reproducible, the effects of conditioning in modulating m-
mune esponses have been "relatively" small, and a recurring question has
been whether behaviorally induced alterations in immunocompetenceave
any biological or clinical significance. So far, only a few studies have ad-
dressed this issue. In a study using mice hat developa systemic upus-erythe-
matosus-like autoimmune isease (Ader & Cohen1982), conditioned stimuli
were substituted for half of the weekly treatments with active im-
munosuppressivedrug (CY). The onset of autoimmune isease in the geneti-
cally susceptible (NZB NZW)F1 ice was thereby delayed using a cumula-
tive dose of CYhat wasnot, by itself, sufficient to alter the progressionof the
lupus-like disease. Also, in lupus-prone mice that had previously been given
weekly reatments with CY paired with the taste of saccharin), reexposure
the CSafter discontinuation of active drug treatment prolonged urvival rela-
tive to conditionedmice that received neither active drug nor reexposure o the
CS (Ader 1985). Analogous esults were obtained in studies of adjuvant-in-
duced arthritis in rats using either CY or cyclosporin as the UCS
(Klosterhalfen & Klosterhalfen 1983, 1990) and electric shock as the UCS
(Lysle et al 1992a), and in a study in which reexposure to a CSpreviously
paired with CY ccelerated mortality among onditioned animals inoculated
with a syngeneic plasmacytomaGorczynskiet al 1985).
Recently the therapeutic potential of conditioning was examined n differ-
ent transplantation models n an effort to prolonggraft survival. A/J recipient
mice typically reject allogeneic skin grafts from BALI3/c r C57BL/6 onors
within two weeks. A low-dose injection of CYon the day of grafting, how-
ever, prolongs graft survival. In mice conditioned by the pairing of saccharin
and CY, reexposure to the CS alone on the day of grafting and at 5-day
intervals thereafter also prolonged urvival of the skin allograft (Gorczynski
1990). In another recent study (Grochowicz t al 1991), reexposure of trans-
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62 ADER & COHEN
1896:45). The literature contains descriptions of several similar cases of what
mayrepresent conditioning phenomena Hill 1930; Smith & Salinger 1933;
Dekker et al 1957). Laboratory studies in humans Dekker et al 1957; Khan
1977) and animals (e.g. Ottenberget al 1958) confirm he clinical suggestions
that exposure to symbolic, nonallergenic stimuli (CSs) previously associated
with allergens are capable of inducing asthmatic symptomsn some ubjects.
More ecent data provide preliminary evidence that conditioning may be
able to modify immune esponses in humansubjects. In a study by Ikemi &
Nakagawa1962), four subjects received cutaneous stimulation with a methy-
lene blue solution (the CS) containing the extract of a Japanese lacquer tree
that unconditionally induced eczemawithin 24 hr. After an unspecified num-
ber of CS-UCSairings, the CS alone elicited a skin reaction in all four
subjects. Smith & McDaniels 1983) also tried to condition a DTHesponse
human ubjects. Healthy volunteers underwent tuberculin skin testing six
times at monthly intervals. In a counterbalanced manner, the "blinded" re-
search nurse administered tuberculin obtained from a green vial to one arm
and saline drawn roma red vial to the other arm. On he test trial, the contents
of the colored vials were switched; neither the experimenter nor the subject
was aware that tuberculin had nowbeen put into the red vial, saline into the
green. Saline administered to the ann that had prcviously been treated with
tuberculin did not evoke a skin reaction, but there was a significant diminution
of the erythema and induration elicited by tuberculin in the arm previously
injected with saline. This finding is remarkablysimilar to that reported by
Moynihan t al (1989) in mice.
The failure of saline to evoke a skin reaction could be instructive, particu-
larly for the strategy underlying such research. First of all, the immunologic
mechanisms hat could dampen n immunologicallyspecific response are not
necessarily the sameas those that might elicit or enhance hat same esponse.
In the case of immunoenhancement, n immunogenicstimulus may be re-
quired, even f it alone is not sufficient to elicit a discernible reaction. Amore
reasonable paradigm for the behavioral modification of an immune esponse,
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PSYCHONEUROIMMUNOLOGY3
ible immuneesponse. This basic strategy was used by Bovbjerget al (1982,
1984) whodemonstrated that the combination of a CSfor immunosuppression
and a low dose of CYdepressed a GvH esponse to a significantly greater
degree than the low dose of CYwas able to accomplishalone.
The anticipatory nausea that occurs in 25-75%of patients undergoing
repeated chemotherapyor cancer appears to reflect a classically conditioned
response (Andrykowski et al 1985, 1988; Andrykowski& Redd 1987; Carey
& Burish 1988; Morrow & Dobkin 1988; Redd & Andrykowski 1982).
Bovbjerg et al (1990) studied womenwho had experienced at least three
sessions of chemotherapyo determine f cancer patients whodisplayed antic-
ipatory nausea and vomiting during the course of chemotherapywouldalso
showanticipatory immunosuppressive hanges. Peripheral blood was obtained
at the patients homes3-8 days before a scheduled chemotherapy ession and
again in the hospital just before the intravenous drug infnsion. Nodifferences
in NK ell activity or in cell counts or cell subset numberswere observed, but
in vitro proliferation in response to the T-cell mitogensPHA nd ConA were
significantly lower prior to chemotherapyhan the responses measured n the
homeenvironment. There was no evidence that the decreased mitogen re-
sponses were related to anticipatory nausea or to the increased anxiety that
occurred in the hospital. This observation of anticipatory immunosuppression
is entirely consistent with the proposition that chemotherapy atients who
receive an immunosuppressiverug under a relatively constant set of environ-
mental conditions would show conditioned changes in immune unction as
well as in behavior. The extent to which these behavioral and immune e-
sponses reflect the same underlying mechanisms--or, s the animal literature
suggests, represent independently conditioned responses--remains to be de-
termined and might prove important in the clinical managementf chemother-
apy patients.
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64 ADER& COHEN
Effects of Stress on Disease
Studies in humans ave mplicated psychosocial actors in the susceptibility to
and/or the progression of a variety of pathophysiologic processes including
bacterial, allergic, and autoimmuneiseases that involve alterations in im-
munologicdefense mechanisms.Specific examples include Epstein-Barr virus
infections, respiratory infections, streptococcal infections, asthma,and arthri-
tis. Comprehensivereatments of this subject have been provided recently by
S. Cohen& Williamson (1991) and Weiner (1977, 1991). Most of the experi-
mental work has been conducted with animals and indicates that a variety of
behavioral manipulationsor stressors can influence susceptibility to a variety
of disease states in a variety of species. However,he stressors used do not all
produce he sameeffects. The impact and direction of the effects of stressful
stimulation depend upon he disease process to which the organism s concur-
rently subjected. For example,physical restraint in rodents increases suscepti-
bility to infection with herpes simplex virus (Bonneau t al 1991a,b; Rasmus-
sen et al 1957 ) and the Maloney arcomavirus (Seifter et al 1973), has
effect on the response to an experimentally induced lymphorna Greenberg et
al 1984), and decreases susceptibility to allergic encephalomyelitis Levine
al 1962). Likewise, electric shock stimulation increases susceptibility to
Coxsackie B virus but decreases susceptibility to malaria (Friedman et al
1965) and to the spontaneous developmentof leukemia in AKRmice (Plaut
al 1981). Using the same disease outcome e.g. encephalomyocarditisvirus),
electric shockstimulation decreases susceptibility but the stimulation of han-
dling has no effect (Friedmanet al 1969); and, while both electric shock and
handling decrease susceptibility to collagen-induced arthritis, a different
stressor, auditory stimulation, increases susceptibility (Rogerset al 1980a,b).
Analogous esults are observed in studies on the development nd progres-
sion of tumors in animals (Justice 1985; Sklar & Anisman 981). Psychosocial
factors can influence the development nd/or growth of tumors, but the direc-
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PSYCHONEUROIMMUNOLOGY5
(including immunologic esponses) induced by specific forms of stressful
stimulation.
While llustrations like those above documenthe effects of stressors on the
response to pathogenic agents, they do not provide evidence that these effects
are mediated by behaviorally induced alterations in immune unction. Too
frequently, however, tudies of the effects of stressors on tumor development
or metastasis are cited as evidence of the influence of stress or behavioral
interventions on immune unction--even in the absence of any measure of
immune unction. Andeven when simultaneous measures of immune unction
are being measured, t is not alwaysclear that the indexes chosen or study are
related to the. pathophysiologicprocess under study. It is not yet clear that
behaviorally induced perturbations in immuneunction can influence or medi-
ate the effects of psychosocial factors on the development r progression of
disease in humans,but provocative data are nowbeing obtained (e.g. Glaser et
al 1987; Kemenyt al 1992), especially in relation to the experimental nocu-
lation of respiratory viruses .(Broadbent et al 1984; S. Cohenet al 1991;
Totman t al 1980).
More ecent animal studies, however, are including biologically relevant
measures of immune unction. Feng et al (1991), for example, infected mice
with influenza virus and observeda delay in the production of virus-specific
antibody levels in animals subjected to restraint. There were no detectable
differences in the magnitudeof the humoral response ultimately attained,
however--a inding that could be related to an interaction between he tempo-
ral relationship of restraint and infection and the virulence of the pathogen
(Chaoet al 1990). At a clinical level, psychosocial actors have been related
the manifestation of latent herpes virus infection (e.g. Glaser et al 1987).
Bonneau t al (1991a), studying the effects of a stressor on the murine re-
sponse to herpes simplex virus (HSV),found that repeated, prolonged periods
of physical restraint (16 hr/day for a varying number f days around the time
of inoculation) suppressed NKcell activity and the primary developmentof
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66 ADER & COHEN
process, forced swimming ecreased NKcell activity and resulted in a two-
fold increase in lung metastases.
Effects of Stress on Humoral and Cell-Mediated Immunity
Unlike the measurementof hormone evels or nonspecific defense reactions
that can be gaugedby sampling actors circulating in blood, urine, saliva, etc,
the assessment of immuneesponses, such as most of those described above n
the context of disease susceptibility, requires that experimental subjects be
immunized.This additional variable adds layers of complexity o the charac-
terization of the effects of behavioral and other interventions on immune
function and the mediation of these effects. In addition to the quality and
quantity of environmentalstimulation and the temporal relationship betweena
stressor and immunization, ne must, for example, consider the nature as well
as the concentration of antigen and the "cascade" of immune vents that
eventuate in the production of antibody or a cell-mediated inflammatory e-
sponse. This complexity s reflected in much f the data describing the effects
of stressful stimulation on different aspects of immuneunction.
The relevance of the concentration of antigen used for immunization in
studies of stress has been noted in the past (Solomon t al 1974). In our view,
studies that address immune unction per se use what might be described as
suprathreshold levels of antigenic stimulation---concentrations of antigen cal-
culated to induce a "robust" primary and secondary response. To the extent
that behaviorally induced neuroendocrine changes are capable of modulating
immune esponses, the use of high levels of antigenic stimulation are not
comparable to the levels of antigen exposure experienced by the organism
under natural conditions and could be counterproductiveas a research strategy
designed to elaborate behaviorally induced alterations in immunocompetence.
For these reasons, Moynihan t al (1990a) studied the effects of a stressor
(electric shock) on the response to low-dose antigenic stimulation. An im-
munizing dose of as little as 1 btg of the protein antigen keyhole limpet
hemacyaninKLH)was insufficient to elicit a detectable primary response but
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PSYCHONEUROIMMUNOLOGY7
and/or secondary antibody responses to several different antigens (e.g.
Cunnick et al 1991; Edwards & Dean 1977; Edwards et al 1980; Glenn &
Becker 1969; Rabin et al 1987a,b; Rabin & Salvin 1987; Solomon 1969;
Vessey 1964). Antibody responses are also suppressed whensubmissive, in-
truder, and attacked and defeated rats are subsequently immunized13eden
Brain 1982, 1984; Fauman 987; Fleshner et al 1989; Ito et al 1983). A recent
review of these data has been provided by Bohus& Koolhaas 1991). Even he
odors emittedby micesubjected to stressful stimulation are sufficient to influ-
ence antibody production in consPeeific recipients. In one study (Zalcmanet
al 1991 a,b), the antibody response to SRBC as suppressed in mice placed
into an apparatus vacated by conspecifics that had been exposed o a presumed
stressor; in another study (Cocke et al 1992), immunizationwith KLHollow-
ing prolonged exposure to alarm signals emitted by conspecifics undergoing
concurrent stimulation enhanced antibody responses in the group-housedre-
cipients.
Antibody esponses are influenced by early separation experiences. In rats,
brief handling and separation from the mother increased both primary and
secondaryantibody responses to flagellin, a bacterial antigen (Solomon t al
1968), In mice, early separations from the mother resulted in a decreased
anti-SRBC ntibody response (Michaut et al 1981), and separation from the
mother and rearing environment influenced the antibody response of monkeys
to an antigenic challenge (e.g. Coeet al 1985, 1988).
Okimura and his colleagues (Okimura & Nigo 1986; Okimura et al
1986b,c) found that serum antibody titers and the numberof antibody-forming
splenic cells of mice were depressed if physical restraint (12 hr/day on two
consecutive days) was imposed after, but not before, immunization with
SRBC, T-cell dependent antigen. 13oth adrenalectomy and chemical sympa-
thectomyblocked the stressor-induced immunosuppression.The response to a
hapten (TNP)conjugated to a type 2 T cell-independent carrier (Ficoll)
not influenced by restraint, but there was enhanced antibody production in
response o a type 1 T cell-independent antigen (LPS). In this case, adrenalec-
tomy, but not sympathectomy,blocked the enhanced response. The differen-
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68 ADER & COHEN
influenced the immuneesponse, but not in the hypothesized direction. Zalc-
manand his colleagues (1988) subjected mice to a single session of footshock
0, 24, 48, 72, or 95 hr after immunization with SRBC.Both the numberof
antibody-forming cells and serum anti-SRBC ntibody titers were depressed,
but only in micesubjected to the stressor 72 hr after immunization, uggesting
that there is a critical period for this acute stressor, at least, on antibody
production. Based on changes in norepinephrine activity within the central
nervous system that result from this sameschedule of electric shock treatment
(Anismanet al 1987; Zacharko & Anisman 988), Zakman t al expected that
"controllability" would have influenced the immune esponse. There were,
however, no differences between mice that were and were not able to escape
the electric shock.
A seemingly innocuous form of stimulation with the immediate and long-
teim ability to influence antibody production is the handling of animals. Moy-
nihan et al (1990b) found that antibody production in response to KLHwas
attenuated in adult mice that were immunized fter a 2-weekperiod of daily
handling. Raymondt al (1986) found that, dependingon strain, rats that were
simply handled during the neonatal period had suppressed antibody titers in
response to subsequent immunization with SRBC. n response to flagellin
administration, adult rats handled during infancy showedan enhanced anti-
body response. In related research, Taylor & Ross (1989) found that neonatal
restraint (1 hr/day during the first 10 days of life) suppressed antibody re-
sponses to immunizationwith pneumococcal olysaccharide in adult rats. In
adult animals, the same restraint imposed for 3 weeksfollowed by a 3-week
interval before immunizationhad no discernible effects.
4
Moynihan nd her
associates (Moynihanet al 1989) subjected mice to a different number
intraperitoneal (ip) injections of saline or just handling during the 2-week
period before the animals were injected with antigen. Daily handling as well
as the repeated ip injections of saline attenuated the productionof antibody in
response to KLHelative to a group of unmanipulated mice. Whether there
was an attenuated response in the manipulated animals or an exaggerated
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PSYCHONEUROIMMUNOLOGY9
immune esponses. Restraint imposedbefore sensitization or challenge sup-
pressed the delayed cutaneous hypersensitivity response to SRBC.Exposure
to cold for two days after sensitization also depressed the DTHesponse,
whereas exposure to cold for eight days increased the DTHesponse. Heat
exposure invariably increased the hypersensitivity response. Contact hyper-
sensitivity to dinitrofluorobenzene was increased by each of these stressors.
Further, adrenalectomyor treatment with metapyrone brogated the stressor-
induced suppression of DTH ut had no effect on the strcssor-induced en-
hancement f the contact sensitivity response. Again, the literature provides
little justification for generalizing fromone stressor to another---or fromone
aspect of immuneunction to another.
Another mmunologicallyelevant reaction to stressors is a suppression of
macrophage unction (Pavlidis & Chirigos 1980; Jiang et al 1990; Okimura t
al 1986a; Qunidoset al 1986; Zwilling et al 1990), which maybe mediated by
a stressor-induced depression of IFN production (Glascr et al 1986;
Sonnenfeld et al 1992). The expression of class II major histocompatibility
complex antigens by macrophages (glycoproteins that, together with pro-
cessed antigen, are presented to and recognized by lymphocytes) was de-
creased by physical restraint (Zwilling et al 1990) and cold water exposure
(Jiang et al 1990); in the study by Sonnenfeld et al (1992), electric shock
suppressed IFN-gamma roduction and the expression of class II antigens
which could, in turn, influence antibody- and cell-mediated immunocompet-
ence.
Effects of Stress on Nonimmunologically Specific Reactions
As in the case of antibody- and cell-mediated immunity, the effects of
stressors on nonspecific defense reactions are generally suppressive, but not
uniformly so (Croiset et al 1987; Lysle et al 1990a,b; Monjan& Collector
1977; Rinneret al 1992; Weisset al 1989b).
The differential housing of rodents results in differences in
lymphoproliferativeresponses to mitogens, NK ell activity, and IL-2 produc-
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70 ADER & COHEN
1992), and as a result of separation experiences (Ackerman t al 1988).
effects of separation experiences from mothers or peers in several nonhuman
primate species can have long-lasting effects (Coe et al 1989; Friedman t al
1991; Gust et al 1992; Laudenslager t al 1985, 1990). Increases and decreases
in lymphocyteproliferation have also been observed in handled animals, de-
pending on the amount of handling and the age at which it is experienced
(Lown& Dutka 1987; Moynihan t al 1990b; Rinner et al 1992). Similarly,
NK ell activity is frequently, but not invariably, depressed following acute
exposure to a variety of stressors (Aarstad et al 1983; Jiang et al 1990;
Moynihan et al 1990a; Okimura et al 1986a; Steplewski & Vogel 1986;
Steplewski et al 1985).
Electric shock stimulation has been the most frequently used stressor in
studies of nonspecifically stimulated defense reactions and thus provides the
more systematic data. Keller and his associates (1981) found that, with in-
creasing intensities of electric shock over a period of 18 hr, there was a
correspondingdecrease in the proliferation of peripheral blood lymphocytesn
response to PHA, even when the assay was based on a constant number of
cells to correct for the stressor-induced decrease in the total number f circu-
lating lymphocytes.Less reliable effects were found in the responseof splenic
lymphocytes, although Weiss et al (1989b), using the same paradigm, found
significant suppression of lymphoproliferation of both splcnic and blood lym-
phocytes. Under hese conditions, they also found a decline in IL-2 and inter-
feron (IFN) production. Batuman t al (1990) obtained essentially the
results varying the number f days of electric shock stimulation and measuring
the response to both Con A and PHA.The proliferative response to B cell
mitogens (pokeweed mitogen and LPS) was not influenced by the stressful
stimulation. These investigators also noted a decrease in the total number f
splenic and peripheral blood lymphocytes,particularly of CD8+ells. In addi-
tion, IL-2 production was diminishedafter as little as one day of exposure o
the 3-hr period of stimulation.
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PSYCHONEUROIMMUNOLOGY 71
The ability to predict or control the effects of stressful stimulation has
become a major focus of stress-related research and, as a result, the effects
obtained by Laudenslager et al (1983) indicating that inescapable but not
escapable footshock depressed mitogen responsiveness in rats has been cited
frequently. Less frequently cited, however, is the report by these investigators
(Maier & Laudenslager 1988) of their inability to reproduce these effects.
contrast to the effects on antibody production, however, Mormedeand his
colleagues (1988) found that "control" did influence the response to mitogens.
Rats subjected to inescapable or unsignaled electric shock stimulation showed
a suppression of the lymphoproliferative response to T-cell mitogens. Also,
preliminary data obtained by Shavit et al (1983) indicated that inescapable but
not escapable shock suppressed splenic NKcell activity in rats. In another
preliminary study (Irwin & Custeau 1989), however, signaled electric shock
resulted in a more pronounced suppression of NKcell activity than unsignaled
shock.
Electric shock stimulation also suppresses NKcell activity (Cunnick et al
1988; Keller et al 1988; Lysle et al 1990a; Lysle & Maslonek 1991; Shavit et
al 1984; Weiss et al 1989b), the kinetics of which are strain dependent in mice
(Zalcman et al 1991a). Shavit and his colleagues (1984, 1986) found
intermittent electric shock stimulation, which induces an opioid-mediated an-
algesia, also depresses NKcytotoxicity, whereas continuous shock, which
results in a nonopioid analgesia, has no such effect.
MEDIATION OF BEHAVIORALLY INDUCED IMMUNE
CHANGES
There are no definitive data on the mediation of behaviorally conditioned or
stressor-induced changes in either specific or nonspecific defense system re-
sponses. It is clear that different immunologic and neuroendocrine mecha-
nisms are involved in mediating the effects of different behavioral interven-
tions on different immune responses measured in different compartments of
the immune system.
The available data suggest that the effects of conditioning could be medi-
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72 ADER & COHEN
The observed ncreases or decreases in the antibody-forming ell response to
SRBC epended on the donor cells and the conditioning treatment experi-
enced by the recipient. The separate transfer of enriched T and B cells into
naive or conditioned mice suggested that conditioning effects were attribut-
able to the adoptively transferred T cells (Gorczynski1991). The question
whetherconditioning can modulate he antibody response to different types of
T-cell independent antigens has not been resolved (N. Cohenet al 1979;
Schulze et al 1988; Wayner t al 1978).
Stressful stimulation also seems o have greater effects on T cell than on B
cell function (e.g. Batuman t al 1990; Lysle et al 1990b; Mormedet al 1988;
Moynihan t al 1990b). Several investigators have demonstrated conditioned
and stressor-induced decreases in IL-2 production that might account for the
suppression of T cell proliferation (e.g. Batuman t al 1990; Ghoneumt al
1988; Hardy et al 1990; Kandil & Borysenko 1988; Weiss et al 1989b).
However, adding IL-2 to incubated lymphocytes did not normalize the
stressor-induced suppression of lymphoproliferation (Weiss et al 1989a).
These investigators did find that electric shock decreased the expression of
IL-2 receptors on lymphocytes, suggesting that a compromisedbility to re-
spond to IL-2 may contribute to stressor-induced immunosuppression and,
via neural and/or endocrine pathways, conditioned antibody- and/or cell-medi-
ated immuneesponses, as well).
The in vitro T cell effects of behavioral nterventions appear to be differen-
tially expressed by splenic and blood lymphocytes n the case of both condi-
tioning (Lysle et al 1990a; Lysle & Maslonek 991) and stressful stimulation
(Cunnicket al 1988; Keller et al 1983, 1988; Lysle et al 1987; Rinner et al
1992). This could reflect the trafficking of lymphocytes nd a resulting differ-
ence in the kinetics of the response in these two compartmentsCunnicket al
1988; Lysle et al 1987); it could also relate to differences in the manner n
which splenic and peripheral blood lymphocyteswere cultured. However, he
fact that there is noradrenergic innervation of the spleen (Felten et al 1987)
and that the stressor-induced suppression of splenic but not blood lymphocyte
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PSYCHONEUROIMMUNOLOGY3
(but not uniformly) immunosuppressive Munck& Guyre 1991). Nonetheless,
an endogenous levation in adrenocortical steroids in response to different
stressors cannot be invoked to account for most of the stressor-induced
changes in immunocompetence.
In terms of antigen-specific immune esponses, Okimuraet al (1986b)
found that adrenalectomy blocked the suppression of antibody responses to
SRBCn rats that had been subjected to restraint, but adrenalectomydid not
influence the immunosuppressiveffects of rotation (Esterling & Rabin 1987).
In studies using electric shock (Laudenslager t al 1988; Mormedet al 1988),
no relationship betweencorticosterone levels and suppressed antibody produc-
tion in rats was seen. Blechaet al (1982b) ound that adrenalectomy ttenuated
the suppression of a DTHesponse in restrained mice but did not affect the
restraint-induced enhancement f contact hypersensitivity. With respect to
nonspecific reactions, electric shock in rats induced a lymphopeniahat was
adrenal dependent (Keller et al 1981); the stressor-induced suppression
mitogen responsiveness, however,was unaffected by adrenalectomy Keller et
al 1983). The suppressed lymphoproliferative response of splenic T lympho-
cytes, in particular, has been shown onsistently to be independentof stressor-
induced adrenal activity (e.g. Lysle et al 1990b; Monjan& Collector 1977;
Mormedet al 1988; Rabin et al 1987a, b; Weisset al 1989b). Thestressor-in-
duced suppression of NK ell activity and IL-2 production are not blocked by
adrenalectomy e.g. Weisset al 1989b).
Both conditioned and stressor-induced alterations of immune nd nonspe-
cific defense responses have been attributed to the actions of catecholamines.
Gorczynski& Holmes 1989), for example, reported that both chlorpromazine
and amitriptyline abolished conditioned immunosuppressiveesponses based
on the pairing of a gustatory stimulus with CY.Lysle et al (1992a) reported
that the [3-adrenergic antagonist propranololblocked he effects of conditioned
stressor effects on the development f adjuvant-induced rthritis; but propran-
olol itself maybe capable of attenuating inflammatoryesponses (Kaplanet al
1980). Cunnickand her colleagues (1990) found that propranolo and nadolol
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74 ADER & COHEN
and, at the same time, suppressed or unaltered serum levels of im-
munoglobulins. In this instance, phentolamine blocked the effects of cold
exposure nd propranololpotentiated the effects of the stressor. While ittle is
known f the immunologic ffects of catecholamines n vivo, it is relevant to
note that Zalcman t al (1991 a) wereunable to detect any meaningful elation-
ship between he depression of brain levels of norepinephrineand the suppres-
sion of NK ell activity induced by one hour of uncontrollable electric shock
stimulation. It is evident that any involvementof catecholamines n the media-
tion of stressor-induced alterations of immunitys determinedby interactions
involving the nature of the immune esponse and the compartment n which it
is measured and the neurochemical concomitants of the adaptive responses
inducedby the nature of the stressor.
Opioids acting within the central nervous system have also been implicated
in the mediation of conditioned and stressor (electric shock)-induced alter-
ations of nonspecific defense responses. Cunnick and her colleagues (1988)
found that naltrexone, an opioid receptor antagonist, blocked a shock-induced
suppression of splenic NKcell activity but did not obviate suppression of the
splenic lymphocyte esponse to T cell mitogens. Lysle et al (1992b) found that
naloxone (in doses higher than those used by Cunnick et al) blocked the
conditioned suppression of NK ell activity and the depressed response to both
T and B cell mitogens. Although he association betweenan olfactory CS and
poly I:C was unaffected, subsequent enhancement f NKcell activity in re-
sponse to reexposure to the CSalso could be blocked by naltrexone (Solvason
et al 1989). N-methylnaltrexone, quaternary form of naltrexone that does not
cross the blood-brain barrier, did not interfere with these conditioned re-
sponses.
That the effects of stressful stimulation on NK ell activity maybe medi-
ated by centrally acting opioids is suggested by the observations that the
immunosuppression nduced by electric shock was prevented by pretreatment
with naltrexone but not by the peripheral actions of N-methylnaltrexone,and
that a dose-dependent suppression of NK ell activity could be induced by
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PSYCHONEUROIMMUNOLOGY5
It mayalso be relevant that some tudies have uncovereddifferent changes
in mitogenesis and/or NKcell activity in animals subjected to avoidable or
unavoidable, escapable or inescapable, or signaled or unsignaled electric
shock (Irwin & Custeau 1989; Mormedet al 1988; Shavit et al 1983), despite
the fact that each of these stressful situations would it the criterion for an
opioid-mediated nalgesia that mightbe expected to suppress NK ell activity.
Other studies (e.g. Cunnick t al 1988; Keller et al 1988; Odioet al 1987)have
noted a dissociation between he effects of the samestressor, electric shock
(albeit of different magnitudes, ntensity, and duration), on NK ell and mito-
gen responses, both of which have been observed to be blocked by naltrexone
treatment in one study (Lysle et al 1992b). There is abundant evidence that
opioids, for which there are receptors on lymphocytes(Blalock 1988), can
influence immuneunctions. It is not likely, however, hat centrally acting
opioids are the sole mediator of either conditioned or stressor-induced alter-
ations of immunocompetence.
The fact that someagonistic or antagonistic neurochemical or pharmaco-
logic intervention can block or mimic he immunologic ffects of reexposure
to a CSor stressful stimulationdoes not, in itself, constitute an explanationof
the behaviorally induced effects. It suggests only that such a pathway s one
(of perhaps several) meansby whichsuch an effect could occur. Indeed, the
complexityof the multiple communication hannels between he brain and the
immune ystem provides any numberof other pathways through which behav-
iorally induced alterations in immunitycould be mediated. It is beyond he
scope of this review, however, o detail these interactions (see Ader et al
199 a); nor, because of the paucity of behavioral data, should we speculate on
their role in the psychophysiologic egulation of immunity.These nteractions
can, however, be summarized s follows.
Primary (thymus, bone marrow)and secondary (spleen, lymphnodes, gut-
associated lymphoid tissues) lymphoidorgans are innervated by the sympa-
thetic nervous system (Felten & Felten 1991), and lymphoid cells bear
receptors for manyneuroendocrine and neurotransmitter signals that have
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76
ADER & COHEN
transmitters can influence immune esponses (e.g. Berczi & Nagy1991; Ader
et al 1990), and that immunologiceactions alter circulating levels of hor-
monesand neurotransmitters (e.g. Besedovsky & dcl Rey 1991); and that
behavioral manipulations e.g. Pavlovian conditioning, stressful stimulation)
can, as described above, ~nodulate antigen-specific and nonspecific immune
responses, that the physiological effects of products of an activated immune
system can be conditioned (Dyck et al 1990), and that immunologic dys-
regulations have behavioral consequences Ader et al 199 lb).
Wecannot yet specify the mechanisms nderlying the functional relation-
ship between the nervous system and the immune system--mechanisms
illustrated by conditioned and stressor-induced modulationsof different com-
ponents of immunological efenses. In fact, for the most part we cannot yet
specify the functional significance of the neuroanatomical, neurochemical,
and neuroendocrine connections between the brain and the immune ystem.
Only in recent years, however, has the autonomyof the immune ystem been
seriously questioned. Behavioral research has played a central and enabling
role in provokingstudies of interactions between he central nervous system
and the immune ystem, and now represents only one of several lines of
research that provide converging support for an integrated approach to an
understanding of adaptive processes.
SUMMARY
The acquisition and extinction of the conditioned suppression or enhancement
of one or another parameter of antigen-specific and nonspecific defense sys-
tem responses have been documented n different species under a variety of
experimental conditions. Similarly, stressful stimulation influences antigen-
specific as well as nonspecific reactions. Moreover, both conditioning and
stressful stimulation exert biologically meaningfuleffects in the sense that
they can alter the development nd/or progression of what are presumed o be
immunologically mediated pathophysiologic processes. These are highly re-
Rev.
Psychol.1993.4
4:53-85.
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PSYCHONEUROIMMUNOLOGY 77
which they are superimposed. Conversely, the efficacy of immunologic de-
fense mechanisms seems to depend on the neuroendocfine environment on
which they are superimposed. We seek to determine when and what im-
munologic (or neuroendocrine) responses could be affected by what neuroen-
docrine (or immunologic) circumstances. We herefore need studies that pro-
vide a parametric analysis of the stimulus conditions, the neuroendocrine
and/or immunologic state upon which they are superimposed, and the re-
sponses that are being sampled.
The neural or neuroendocrine pathways involved in the behavioral alter-
ation of immune esponses are not yet known. Both conditioning and stressor-
induced effects have been hypothesized to result from the action of
adrenocortical steroids, opioids, and catecholamines, amongothers. Indeed, all
of these have been implicated in the mediation of some immunologic effects
observed under some experimental conditions. Weassume that different con-
ditioning and stressful environmental circumstances induce different constel-
lations of neuroendocrine responses that constitute the milieu within which
ongoing immunologic reactions and the response to immunologic signals
occur. Based on the complexity of the network of connections and regulatory
feedback loops between the brain and the immune system, these processes
appear to involve both neural and endocrine signals to the immunesystem and
signals from the immunesystem that are received by the nervous system and
provoke further neural and endocrine adjustments. Considering the variety of
immunologic processes involved, it does not seem likely--or biologically
adaptive--that there would be any single mediator of the diverse effects of
either conditioning or stressful stimulation. It does not seem likely, however,
that the ultimate elaboration of the mechanisms underlying behaviorally in-
duced alterations of immune unction will have important clinical and thera-
peutic implications.
ACKNOWLEDGMENTS
Preparation of this review was supported by a USPHSResearch Scientist
Award (K05 MH-06318) to R.A.
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1993.44:53-85.Downloadedfromarjournals.a
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