Psychoneuroimmunology

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Annu. Rev. Psychol. 1993. 44:53-85
Copyright © 1993 by Annual Reviews Inc. All rights reserved
PSYCHONEUROIMMUNOLOGY:
CONDITIONING AND STRESS
Annu. Rev. Psychol. 1993.44:53-85. Downloaded from www.annualreviews.org
Access provided by University of Reading on 12/29/14. For personal use only.
Robert Ader and Nicholas Cohen
Department of Psychiatry and Microbiology and Immunology, University of Rochester

School of Medicine and Dentistry, Rochester, New York 14642
KEYWORDS: psychoneuroimmuno!ogy, conditioning, stress
CONTENTS
INTRODUCTION ''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''"""'"'''''''''''''''''' 53
CONDITIONED MODULATION OF IMMUNITY................................................................ 54
Effects of Conditioning on Humoral and Cell-Mediated immunity..................... 55
Effects of Conditioning on Nonimmunologically Specific Reactions . . . .. . . ....... . ... 59
Antigen as Unconditioned Stimulus . .. . . . . . . .. . . . ... .....
.. . . . . .. . .
............. . ......... .. ....... .. . . . 60
Biologic Impact of Conditioned Changes in Immunity........................................ 61
Conditioning in Human Subjects .. . . . . . . .. . . .
...... .. . .
. . .. .
................ . ............ . .. ........ .. ... 61
STRESS AND IMMUNITY.................................... ............... ................................................... 63
Effects of Stress on Disease................................................................................. . 64
Effects of Stress on Humoral and Cell-Mediated Immunity .............................. . . 66
Effects of Stress on Nonimmunologically Specific Reactions ............................ .. 69
MEDIATION OF BEHAVIORALLY INDUCED IMMUNE CHANGES ............................ .. 71
SUMMARY .............................................................................................................................. 76
INTRODUCTION
During the past 10-15 years, psychoneuroimmunology-the study of the in

teractions among behavior, neural and endocrine function, and immune pro
cesses-has developed into a bona fide field of interdisciplinary research
(Ader 1981a, 199 Ia). Previously unknown and unsuspected connections be
tween the brain and the immune system provide a foundation for the now
numerous observations both (a) that the manipulation of neural and endocrine
functions alters immune responses, and the antigenic stimulation that induces
an immune response results in changes in neural and endocrine function and
(b) that behavioral processes are capable of influencing immunologic reactiv-

53
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54 ADER & COHEN
ity and, conversely, the immune status of an organism has consequences for
behavior. This new research indicates that the nervous and immune systems,
the two most complex systems involved in the maintenance of homeostasis,
represent an integrated mechanism contributing to the adaptation of the indi
vidual and the species. Psychoneuroimmunology emphasizes the functional
significance of the relationship between these systems-not in place of, but in
addition to the more traditional disciplinary analysis of the mechanisms gov
erning functions within a single system.
The range of phenomena that bears on the relationship between behavior
and immunity is quite broad, and no attempt will be made to provide even a
cursory summary of all this literature. We focus here on animal studies of the
effects of conditioning and stress in the modulation of immune function. There

are several more or less programmatic lines of research in humans that the
reader may wish to explore. These deal with the immunologic correlates of
emotional states (primarily depression), personality traits as modulators of
immune function, and the effects of stress on immune function. Few general
izations are possible based on currently available data. Although there is no
definitive evidence for the implied chain of events, the hypothesis that im
mune function may mediate the effects of psychosocial factors on the suscepti
bility to or progression of some disease processes remains tenable. We confine
this review, however, to the experimental literature on the modulation of
immunity by stress and conditioning. Other recent reviews (e.g. S. Cohen &
Williamson 1 99 1 ; Geiser 1989; Kemeny et al 1992; O'Leary 1 990) have dealt
with personality and emotional factors and immunity and/or disease. Some of
these have included an introductory outline of the immune system; an exten
sive treatment of immune function can be found in any of several recent texts
(e.g. Stites & Terr 1991).
CONDITIONED MODULATION OF IMMUNITY
Immune responses, like other physiological processes, can be modified by

classical conditioning. Conditioned modulation of host defense mechanisms
and antigen-specific immune responses were first explored by Russian investi
gators and followed the Pavlovian conditioning principles and procedures of
the day (Metal'nikov & Chorine 1926, 1928). Typically, multiple pairings of a
conditioned stimulus (CS; e.g. heat, tactile stimulation) were paired with injec
tions of a foreign protein, the unconditioned stimulus (UCS); subsequent
presentation of the CS alone was reported to elicit conditioned increases both
in a variety of nonspecific defense responses and in antibody production.
There were English language reviews of this literature (Hull 1934; Kopeloff
194 1), but they apparently attracted little attention, probably owing to the
nascent state of immunology at the time and to the fact that by today's
standards most of these early animal experiments were inadequately de
scribed, poorly designed, lacked appropriate control groups, and constituted
PSYCHONEUROIMMUNOLOGY 55
little more than preliminary observations. Although the data on specific anti
body responses were not convincing, the studies of nonspecific cellular events
(e.g. changes in leukocyte number, phagocytosis, inflammatory responses)
were consistent and provided provocative evidence that conditioning could
modulate host defenses. A detailed review (and some reanalyses) of these data
was provided by Ader (1981b).
Effects of Conditioning on Humoral and Cell-Mediated

Immunity
One of the hallmarks of the immune system's defense of the organism against
foreign, "nonself' material (antigens) is its specificity-its ability to recognize
precisely and then eliminate only the antigens it has confronted. These activi
ties are carried out by a variety of white blood cells (leukocytes). Prominent
among these are T and B lymphocytes that are capable of clonal proliferation
in response to antigens and retaining the "memory" of that encounter. Hu
moral or antibody-mediated immunity involves the exposure of antigens to
bone marrow-derived B cells. These cells effect the ultimate production of
antibodies that protect the organism against extracellular microorganisms and
reinfection. Cell-mediated immunity is provided by thymus-derived T cells
that protect against intracellular parasitic and viral infections. An integrated
immune response to antigens, however, involves complex interactions among
specialized subpopulations of T cells (i.e. helper, suppressor, cytotoxic), B
cells, other white blood cells such as macrophages, and substances (cytokines)
that are secreted by activated leukocytes. A variety of techniques have been
developed to measure these cellular interactions in vitro. The essence of psy
choneuroimmunology, however, is the recognition that in vivo these reactions
occur within a neuroendocrine milieu that is demon strably sensitive to the
organism's perception of and adaptation to events occurring in its environ
ment.
HUMORAL IMMUNITY Current interest in conditioned changes in immunologic

reactivity began with a study by Ader & Cohen ( 1975). Using a taste aversion
conditioning paradigm, a saccharin-flavored drinking solution, the CS, was
paired with an injection of cyclophosphamide (CY), an immunosuppressive
UCS. All rats were subsequently immunized with sheep red blood cells (SRBC).
Antibody titers were measured in conditioned animals that were injected with
CY on the day of immunization (to define the unconditioned immunosuppress
ive effects of CY), in conditioned animals that were not reexposed to the CS (to
assess the influence of prior conditioning and the residual effects of CY), and
in conditioned animals that were reexposed to the CS on the day of immuniza
tion and/or three days later (the critical experimental group). Subgroups of
(nonconditioned) animals were injected with CY following the drinking of plain
water before immunization and were subsequently provided with the presum
ably neutral saccharin solution whenever a comparable subgroup of conditioned
56 ADER & COHEN
animals received saccharin. A placebo-treated group was injected with vehicle

after consuming saccharin or water before immunization and was exposed to
saccharin after immunization. As expected, conditioned animals showed an
aversion to the saccharin solution that had been paired with CY. Conditioned
animals that were reexposed to the CS at the time of, and/or three days after,
immunization also showed an attenuated anti-SRBC antibody response relative
either to conditioned animals that were not reexposed to saccharin or to
nonconditioned animals that were similarly exposed to saccharin . These results
were interpreted as reflecting a conditioned immunosuppressive response. The
acquisition and the experimental extinction of a conditioned suppression and/or
enhancement of antibody- and cell-mediated immune responses as well as
nonspecific host defenses have now been observed under a variety of experi
mental conditions. Only a brief overview of this research is provided here; more
detailed reviews are available elsewhere (Ader & Cohen 1985, 1991).
In the conditioned taste aversion paradigm, animals learn to avoid flavored
solutions previously paired with the noxious or illness-inducing effects of a
variety of (pharmacologic) agents; that is, they reduce their consumption of
the CS solution. Therefore, to obviate the conflict ("stress") induced by having
either to drink a solution paired with illness or to remain thirsty-and to
equate total fluid consumption among differentially treated animals--condi
tioning can be assessed with a two-bottle preference procedure that permits the
animal to choose between plain water and the flavored CS solution. Under
these conditions, conditioned alterations of humoral (e.g. Ader et al 1982;
Bovbjerg et al 1987b; N. Cohen et a11979) and cell-mediated (Bovbjerg et al
1982, 1984) immune responses are still obtained. The available literature
reveals no consistent relationship between conditioned behavioral (aversive)
responses and conditioned immune changes in the taste aversion learning
paradigm; taste aversions can be expressed without concomitant changes in
humoral immunity, and conditioned changes in immune function can be ob
tained without observable conditioned avoidance responses (Ader & Cohen
1975; Ader et al 1987; Bovbjerg et al 1987b ; Gorczynski 1987; Gorczynski et
a11984 ; Rogers et a11976; Schulze et a11988; Wayner et alI978). Moreover,
reexposure to the CS before rather than after immunization with SRBC also
depresses in vivo antibody production (Ader et al 1982; Schulze et al 1988;
Kusnecov et al 1988). The latter results suggest that an antigen-activated
immune system is not necessary for the conditioning of an immunosuppress
ive response .
Conditioned immunomodulatory effects are not confined to the use of CY
or the taste aversion conditioning situation. Conditioned changes in various
parameters of immunologic reactivity have been observed using other im
munomodulating substances (e.g. Ader & Cohen 1981; King et al 1987;
Kusnecov et a1 1 983; see also Hiramoto et a1 1 987; Husband et al 1987). It is
not even necessary to use immunopharmacologic agents as UCSs; evidence
for a conditioned suppression of antibody-mediated responses has been ob-
tained using electric shock as the UCS (Sato et al 1984; Za1cman et al 1989,
1991b).
There have been a few studies in which there were no observable condi
tioned effects (Krank & MacQueen 1988; MacQueen & Siegel 1989). For
theoretical reasons (see Eikelboom & Stewart 1982), these experiments were
conducted with the expectation of observing "paradoxical" or compensatory
conditioned responses (responses opposite in direction to the unconditioned
response). In conditioned animals reexposed to a CS previously paired with
CY, the anti-SRBC antibody response was higher than the response of condi
tioned animals that were not reexposed to the CS and the response of animals
that experienced unpaired CS-UCS presentations, but the responses of condi
tioned animals reexposed to the CS did not differ from those of a saline-treated
control group. Such results may permit one to infer the existence of a condi
tioned enhancement of antibody production based on the failure to observe
immunosuppression, but, as the investigators acknowledge, no direct evidence
of compensatory conditioning was obtained. There is no obvious explanation
for the difference between these results and those in the rest of the literature on
conditioned immunologic changes.
Evidence for the existence of the compensatory conditioning of host de
fense reactions, however, can be derived from studies on the role of condition
ing in the development of pharmacological tolerance to repeated injections of
polyinosinic-polycytidylic acid (poly I:C; Dyck et al 1986, 1987). In keeping
with a conditioning analysis of the development of tolerance to some other
pharmacologic agents (Siegel 1983), tolerance to the enhancing effects of poly
I:C on natural killer cell activity is abrogated by unreinforced exposures to the
CS; preexposure to the CS interferes with the development of tolerance; and
tolerance is attenuated when poly I:C is injected in the absence of environmen
tal cues previously paired with injections of the drug.
CELL-MEDIATED IMMUNITY The immunosuppressive effects ofCY can also be

used to condition changes in cell-mediated responses. In the studies by Bovbjerg
et al (1982,1984), (Lewis x Brown Norwegian)Fl rats were injected with Lewis
l
strain spleen cells to induce a local graft vs host (GvH) response. The basic
experimental protocol used by Ader & Cohen (1975) was modified so that: (a)
there was a 7-week interval between conditioning of the FI hybrid hosts and
injecting them with donor cells (at which time there were no detectable residual
effects of CY), and (b) experimental animals were reexposed to the CS in the
context of reexposure to a minimally effective injection of CY. (The Lewis x
Brown N orwegian)F 1 rats were first conditioned by pairing saccharin consump
tion and CY and were subsequently injected ("grafted") with splenic leukocytes
When splenic leukocytes from an inbred strain of Lewis rats are injected into the footpad of
hybrid (Lewis X Brown Norwegian)Fl rats, the grafted cells recognize the host as "foreign," and a
local int1ammatory reaction (the GvH response) ensues and can be measured by weighing the
popliteal lymph node that drains the injection site.
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 response, a single injection on Day 1
caused only a modest decrease in the response. However, a single low-dose
injection of CY plus reexposure to the CS previously paired with CY signifi
cantly suppressed the GvH response relative to control groups that received only
the single low-dose injection of CY. As expected, unreinforced exposures to the
CS during the 7-week interval between conditioning and induction of the GvH
response resulted in extinction of the conditioned immunosuppressive response.
Experimental extinction, one hallmark of a conditioned response, has also been
reported f or other c onditioned immunologic effects (Dyck et al 1986 ;
Gorczynski et a1 1982; see also Lysle et aI 1988).

Cyclophosphamide can enhance as well as suppress immunologic reactiv
2
ity. In the case of a delayed-type hypersensitivity (DTH) reaction to SRB C ,
low-dose treatment with C Y a t the time of sensitization can enhance DTH i n
response to a subsequent challenge with the same antigen (Turk & Parker
1982) ; C Y treatment of sensitized animals just before antigenic challenge
decreases the DTH response (Gill & Liew 1978; Rodinone et al 1983). Al
though CY decreases the DTH 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 C S
before their initial challenge. However, reexposing conditioned animals t o 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 C S
previously paired with levamisole (Husband e t a l 1987) could b e the phenom
enological expression of a conditioned immunosupprcssive response. Such an
interpretation would be consonant with data suggesting that T cell-dependent
reactions are especially sensitive to conditioning.
As in the case of antibody-mediated immune responses, conditioned
changes involving cell-mediated immunity are not confined to the use of the
taste aversion conditioning model. Mice exposed to a novel environment plus
a distinctive taste in conjunction with rotation on a turntable (the UCS) show a
decreased ability to reject allogeneic skin grafts when reexposed to the com
pound CS at the time of and following the antigenic challenge (Gorczynski
1992). In addition, when conditioned females (mated with nonconditioned
2
DTH is an in vivo inflammatory 'reaction mediated by sensitized T cells tbat is evoked by
contact with tbe antigen with which the animal had been immunized.
males) were reexposed to the CS on Days 13, 16, and 19 of gestation, there
was a depression of humoral and cell-mediated immunity in their un
manipulated offspring.
Effects of Conditioning on Nonimmunologically Specific

.
Reactions
In addition to studying antibody- and cell-mediated immunity, immunologists
also study the nonimmunologically specific in vitro actions of natural killer
cells and mitogens. These are among the most frequently used measures in
behavioral experiments. Natural killer (NK) cells are large granular lympho
cytes that nonspecifically attack and destroy certain virus-infected cells and
tumor cells and may be involved in preventing tumor metastasis.

T and/or B lymphocytes can be induced to proliferate in vitro by stimula
tion with various lectins (chemical substances obtained from plants), and the
lymphoproliferative response to such mitogens has been used to indicate an
alteration of the physiological state of T or B cells in a particular lymphoid
compartment (e.g. spleen , lymph nodes, peripheral blood). Changes in mito
genic responsiveness, however, do not necessarily reflect an organism's abil
ity to respond to antigens in vivo or in an immunologically specific manner.
In a comprehensive series of experiments, Lysle and his colleagues ( 1988,
1990a,b, 1991, 1992b) characterized the conditioned suppression of a variety
of nonspecific responses in rats reexposed to cues previously paired with
stressful stimulation. Compared to nonconditioned animals, to conditioned
animals exposed to novel environmental cues, and to animals exposed to cues
explicitly unpaired with the ues, animals reexposed to auditory (or visual)
cues paired with electric shock stimulation showed a reliable suppression of
lymphoproliferative responses to concanavalin A (Con A) and phytohemag
glutinin (PHA) (two T cell mitogens) , lipopolysaccharide (LPS) (a B cell
3
mitogen), interleukin-2 (IL-2) production, and NK cell activity. As expected,
exposure to the CS before conditioning retarded development of the condi
tioned response, and unreinforced exposures to the CS resulted in experimen
tal extinction (Lysle et al 1988). In addition, the conditioned responses varied
as a function of both the timing of reexposure to the CS in relation to the time
of conditioning and the immune compartment from which the cells were
obtained (Lysle et al 1990a,b; Lysle & Maslonek 1991). In splenic lympho
cytes there was a depressed response to T and B cell mitogens ; in whole blood,
there was a suppression of the response to Con A and PHA, but not to LPS;
Macrophages and activated lymphocytes produce soluble products (cytokines), such as interleu
kino! (IL-!), IL-2, interferons, and tumor necrosis factor that are involved in the proliferation,
differentiation, and effector functions of lymphocytes. In addition, they serve as "im
munotransrnitters" in the sense that some, if not all of them have effects within the central nervous
system and stimulate the release of hormones.
60 ADER & COHEN
cells obtained from mesenteric lymph nodes showed no effects of es reexpos

ure.
Using e ither a taste or odor aversion conditioning paradigm or a stressor as
the ues, other studies have also observed the conditioned suppression of
lymphoproliferative responses both to mitogenic stimulation (Drugan et al
1 986 ; Kusnecov et al 1988; Ne veu et al 1986, 1 987), NK cell activity
(Gorczynski et al 1984; Hiramoto et al 1 987; Lysle & Maslonek 1 99 1 ;
O'Reilly & Exon 1986), and total white blood cell count (Klosterhalfen &
Klosterhalfen 1 987). The conditioned enhancement of NK cell activ ity has
also been reported (Hiramoto et al 1987; Solvason et a1 1988, 199 1 ). However,
some of these latter studies suffer from major design flaws, and others have
been unable to repeat these observations (Ader & Cohen 199 1 ).
In a recent study, Coussons et al (1992) paired exposure to a distinctive

environmental setting with injections of morphine (which unconditionally
suppresses several nonspecific immune responses). Reexposure to the envi
ronmental cues resulted in a conditioned suppression of splenic and peripheral
blood lymphocyte response to T and B cell mitogens, splenic NK cell activity,
and IL-2 production. These results are of additional interest in relation to the
issue of compensatory conditioning discussed above. The conditioned re
sponse mimicked the unconditioned response rather than inducing an opposite
or compensatory response ; induction of such a compensatory response, how
ever, characterizes some of the other behavioral and physiological effects of
morphine (e.g. Siegel 1976, 1983).
As is the case w ith antibody-mediated responses , the above studies uncov
ered no consistent relationship between conditioned behavioral responses and
conditioned changes in nonspecific defense reactions (Klosterhalfen &
Klosterhalfen 1987; Kusnecov et a1 1 988; Neveu et al 1986, 1987; Solvason et
aI 1988).
Antigen as Unconditioned Stimulus
In behavioral terms, an antigen is an unconditioned stimulus for activation of

the immune system and has been used as the DCS in a few studies. A condi
tioned release of h istamine, a nonspecific mediator of an allergic reaction,
occurred in response to a CS associated w ith the injection of the antigen,
bovine serum albumin (Dark et al 1987; Peeke et al 1987; Russell et al 1984),
and an increase in mast cell protease II was observed in sensitized rats
reexposed to environmental cues previously paired with exposure to egg albu
min (MacQueen et al 1 989). With respect to an immune response, per se,
Gorczynski and his colleagues (Gorczynski et al 1982) repeatedly grafted
mice w ith allogeneic skin under a constant set of environmental conditions.
When these mice were given sham transplantations, there was an increase in
the number of precursor cytotoxic T lymphocytes. Subsequent unreinforced
exposures to the graft procedures resulted in extinction of the conditioned
response. These experiments are among the relatively few that have addressed
conditioncd immune responses as distinct from conditioned im

munopharmacologic effects.
Biologic Impact of Conditioned Changes in Immunity

Although highly reproducible, the effects of conditioning in modulating im
mune responses have been "relatively" small, and a recurring question has
been whether behaviorally induced alterations in immunocompetence have
any biological or clinical significance. So far, only a few studies have ad
dressed this issue. I n a study using mice that develop a systemic lupus-erythe
matosus-like autoimmu ne disease CAder & Cohen 1982), conditioned stimuli
were substituted for half of the weekly treatments with active im
munosuppressive drug (CY). The onset of autoimmune disease in the geneti

cally susceptible (NZB x NZW)Fl mice was thereby delayed using a cumula
tive dose of CY that was not, by itself, sufficient to alter the progression of the
lupus-like disease. Also, in lupus-prone mice that had previously been given
weekly treatments with CY (paired with the taste of saccharin), reexposure to
the CS after discontinuation of active drug treatment prolonged survival rela
tive to conditioned mice that received neither active drug nor reexposure to the
CS ( Ader 1985). Analogous results were obtained in studies of adjuvant-in
duced arthritis in rats using either CY or cyclosporin as the UCS
(Klosterhalfen & Klosterhalfen 1983, 1 990) and electric shock as the UCS
(Lysle et al 1992a), and in a study in which reexposure to a CS previously
paired with CY accelerated mortality among conditioned animals inoculated
with a syngeneic plasmacytoma (Gorczynski et aI 1 985).
Recently the therapeutic potential of conditioning was examined in differ
ent transplantation models in an effort to prolong graft survival. AlJ recipient
mice typically reject allogeneic skin grafts from BALB/c or C57BLl6 donors
within two weeks. A low-dose injection of CY on the day of grafting, how
ever, prolongs graft survival. In mice conditioned by the pairing of saccharin
and CY, reexposure to the CS alone on the day of grafting and at 5-day
intervals thereafter also prolonged survival of the skin allograft (Gorczynski
1990). In another recent study (Grochowicz et al 199 1), reexposure of trans
plant recipient rats to a CS previously paired with cyclosporin A extended the
survival of a heterotopic heart transplant. Experiments such as these hint at the
potential clinical significance of conditioned alterations in immune function.
Conditioning in Human Subjects

"As early as 1 557, Amatus Lusitanus related the case of a Dominican monk,
who, whenever he perceived the odor of roses or saw them at a distance, was
immediately seized with syncope and fell unconscious to the ground" (Mac
kenzie 1896:5 1, italics added). Mackenzie described his ability to provoke
asthmatic symptoms by presenting an artificial rose to an allergic patient,
which "forcibly illustrates the role of purely psychical impressions in awake n
ing the paroxysms of the disease familiarly known as 'rose cold'" (Mackenzie
62 ADER & COHEN
1896:45). The literature contains descriptions of several similar cases of what

may represent conditioning phenomena (Hill 1930; Smith & Salinger 1933;
Dekker et al 1957). Laboratory studies in humans (Dekker et a1 1957; Khan
1977) and animals (e.g. Ottenberg et a11958) confirm the clinical suggestions
that exposure to symbolic, nonallergenic stimuli (CSs) previously associated
with allergens are capable of inducing asthmatic symptoms in some subjects.
More recent data provide preliminary evidence that conditioning may be
able to modify immune responses in human subjects. In a study by Ikemi &
Nakagawa ( 1962), four subjects received cutaneous stimulation with a methy
lene blue solution (the CS) containing the extract of a Japanese lacquer tree
that unconditionally induced eczema within 24 hr. After an unspecified num
ber of CS-UCS pairings, the CS alone elicited a skin reaction in all four
subjects. Smith & McDaniels ( 1983) also tried to condition a DTH response in
human subjects. Healthy volunteers underwent tuberculin skin testing six
times at monthly intervals. In a counterbalanced manner, the "blinded" re
search nurse administered tuberculin obtained from a green vial to one arm
and saline drawn from a red vial to the other arm On the test trial, the contents
.
of the colored vials were switched; neither the experimenter nor the subject
was aware that tuberculin had now been put into the red vial, saline into the
green. Saline administered to the arm that had prcviously been treated with
tuberculin did not evoke a skin reaction, but there was a significant diminution
of the erythema and induration elicited by tuberculin in the arm previously
injected with saline. This finding is remarkably similar to that reported by
Moynihan et al ( 1989) in mice.
The failure of saline to evoke a skin reaction could be instructive, particu
larly for the strategy underlying such research. First of all, the immunologic
mechanisms that could dampen an immunologically specific response are not
necessarily the same as those that might elicit or enhance that same response.
In the case of immunoenhancement, an immunogenic stimulus may be re
quired, even if it alone is not sufficient to elicit a discernible reaction. A more
reasonable paradigm for the behavioral modification of an immune response,
then, may require the application of a minimally effective immunogenic stim
ulus-one barely able to elicit a measurable response but sufficient to initiate
some early event in the immunologic cascade that leads to a typical immune
reaction. If "subthreshold" stimulation is capable of being potentiated by an
alteration of the neural and/or endocrine environment in which immune re
sponses occur, one might be more likely to observe a behaviorally induced
alteration in immunologic reactivity under immunogenic stimulus conditions
that actually approximate natural conditions. Thus, in the present example, a
sensory stimulus (e.g. saline) that does not affect the immune system directly
may not suffice to elicit a tuberculin-induced skin reaction. But the superimpo
sition of an immunologically neutral stimulus previously paired with activa
tion of the immune system or the response induced by what would ordinarily
be a subthreshold immunogenic stimulus may be sufficient to elicit a discern-
ible immune response . This basic strategy was used by Bovbjerg et al (1982,
1984) who demonstrated that the combination of a CS for immunosuppression
and a low dose of CY depressed a GvH response to a significantly greater
degree than the low dose of CY was able to accomplish alone.
The anticipatory nausea that occurs in 25-75% of patients undergoing
repeated chemotherapy for cancer appears to reflect a classically conditioned
response (Andrykowski et al 1985, 1988; Andrykowski & Redd 1987; Carey
& Burish 1988; Morrow & Dobkin 1988; Redd & Andrykowski 1982).
Bovbjerg et al (1990) studied women who had experienced at least three
sessions of chemotherapy to determine if cancer patients who displayed antic
ipatory nausea and vomiting during the course of chemotherapy would also
show anticipatory immunosuppressive changes. Peripheral blood was obtained

at the patients' homes 3-8 days before a scheduled chemotherapy session and
again in the hospital just before the intravenous drug infusion. No differences
in NK cell activity or in cell counts or cell subset numbers were observed, but
in vitro proliferation in response to the T-cell mitogens PHA and Con A were
significantly lower prior to chemotherapy than the responses measured in the
home environment. There was no evidence that the decreased mitogen re
sponses were related to anticipatory nausea or to the increased anxicty that
occurred in the hospital. This observation of anticipatory immunosuppression
is entirely consistent with the proposition that chemotherapy patients who
receive an immunosuppressive drug under a relatively constant set of environ
mental conditions would show conditioned changes in immune function as
well as in behavior. The extent to which these behavioral and immune re
sponses reflect the same underlying mechanisms-or, as the animal literature
suggests, represent independently conditioned responses-remains to be de
termined and might prove important in the clinical management of chemother
apy patients.
STRESS A ND IMMUNITY
In the present context, "stress" refers to any natural or experimentally con

trived circumstances that (intuitively, at least) pose an actual or perceived
threat to the psychobiological integrity of the individual. In nonhuman ani
mals, environmental conditions that are apparently perceived as a threat to the
organism, and to which the organism cannot adapt, are accompanied by both
transient and relatively long-lasting psychophysiologic changes. We presume
that these changes contribute to the development of disease, especially if the
organism is at the same time exposed to potentially pathogenic stimuli. As
described below, however, the stress response is not uniformly detrimental to
the organism.
64 ADER & COHEN
Effects o f Stress on Disease

Studies in humans have implicated psychosocial factors in the susceptibility to
and/or the progression of a variety of pathophysiologic processes including
bacterial, allergic, and autoimmune diseases that involve alterations in im
munologic defense mechanisms. Specific examples include Epstein-Barr virus
infections, respiratory i nfections, streptococcal infections, asthma, and arthri
tis. Comprehensive treatments of this subject have been provided recently by
s. Cohen & Williamson ( 199 1) and Weiner ( 1977, 199 1). Most of the experi
mental work has been conducted with a nimals and indicates that a variety of
behavioral manipulations or stressors can influence susceptibility to a variety
of disease states in a variety of species. However, the stressors used do not all
produce the same effects. The impact and direction of the effects of stressful
stimulation depend upon the disease process to which the organism is concur
rently subjected. For example, physical restraint in rodents increases suscepti
bility to infection with herpes simplex virus (Bonneau et al 199 1a,b; Rasmus
sen et al 1957 ) and the Maloney sarcoma virus (Seifter et al 1973), has no
effect on the response to an experimentally induced lymphoma (Greenberg et
al 1984) , and decreases susceptibility to allergic encephalomyelitis (Levine et
a1 1962). Likewise, electric shock stimulation increases susceptibility to
Coxsackie B virus but decreases susceptibility to malaria (Friedman et al
1965) and to the spontaneous development of leukemia in AKR mice (Plaut et
al 198 1). Using the same disease outcome (e.g. e ncephalomyocarditis virus),
electric shock stimulation decreases susceptibility but the stimulation of han
dling has no effect (Friedman et al 1969) ; and, while both electric shock and
handling decrease susceptibility to collagen-induced arthritis, a different
stressor, auditory stimulation, increases susceptibility (Rogers et al I 980a,b).
Analogous results are observed in studies on the development and progres
sion of tumors in a nimals (Justice 1985; Sklar & Anisman 1981). Psychosocial
factors can influence the development and/or growth of tumors, but the direc
tion of the effects depends on the tumor model chosen for study. The results
also depend on the quality, quantity, and duration of the stressor; the temporal
relationship between exposure to the stressor and the introduction of patho
genic stimulation; socioenvironmental conditions (e.g. whether animals are
housed individually or in groups) ; and a variety of host factors (e.g. species,
strain, and sex). Further, the observed effects depend on the outcome measures
a nd sampling parameters selected for study. As described below, the effects of
stressful stimulation on immune function parallel those on stressful stimula
tion and disease susceptibility. It seems evident-or, at least likely-that the
ability to predict the outcome of studies of the pathophysiologic effects of
stressful stimulation depends upon a more detailed u nderstanding of the inter
action between responses unconditionally elicited by specific kinds of poten
tially pathogenic stimulation and the pattern of psychophysiological responses
(including immunologic responses) induced by specific forms of stressful

stimulation.
While illustrations like those above document the effects of stressors on the
response to pathogenic agents, they do not provide evidence that these effects
are mediated by behaviorally induced alterations in immune function. Too
frequently, however, studies of the effects of stressors on tumor development
or metastasis are cited as evidence of the influence of stress or behavioral
interventions on immune function-even in the absence of any measure of
immune function. And even when simultaneous measures of immune function
are being measured, it is not always clear that the indexes chosen for study are
related to the pathophysiologic process under study. It is not yet clear that
behaviorally induced perturbations in immune function can influence or medi

ate the effects of psychosocial factors on the development or progression of
disease in humans, but provocative data are now being obtained (e.g. Glaser et
al 1987; Kemeny et al 1992), especially in relation to the experimental inocu
lation of respiratory viruses (Broadbent et al 1984; S. Cohen et al 1991;
Totman et aI 1980).
More recent animal studies, however, are including biologically relevant
measures of immune function. Feng et al ( 199 1 ), for example, infected mice
with influenza virus and observed a delay in the production of virus-specific
antibody levels in animals subjected to restraint. There were no detectable
differences in the magnitude of the humoral response ultimately attained,
however-a finding that could be related to an interaction between the tempo
ral relationship of restraint and infection and the virulence of the pathogen
(Chao et aI 1990). At a clinical level, psychosocial factors have been related to
the manifestation of latent herpes virus infection (e.g. Glaser et aI 1987).
Bonneau et al ( 199 1a), studying the effects of a stressor on the murine re
sponse to herpes simplex virus (HSV), found that repeated, prolonged periods
of physical restraint ( 16 hr/day for a varying number of days around the time
of inoculation) suppressed NK cell activity and the primary development of
HSV-specific cytotoxic T lymphocytes. Also, higher titers of infectious HSV
at the site of infection were recovered from restrained than from unrestrained
mice. Similar results were obtained by Ku snecov et al ( 1992) using overnight
exposure to intermittent electric shock stimulation ( 1 shock every 30 min, on
average) on the day preceding and for eight days following virus infection. In
another study (Bonneau et al 199 1b), restraint inhibited the in vitro activation
and/or migration of HSV-specific cytotoxic T lymphocytes from previously
primed mice-i.e. activation of HSV-specific memory cells was inhibited by
the physiological changes induced by the stressor. Other examples relate to
neoplastic disease (Ben-Eliyahu et a1 199 1 ; Brenner et aI 1990). Using a tumor
model in which lung metastasis is thought to be controlled by NK cells,
Ben-Eliyahu and his colleagues ( 199 1 ) found that, depending upon when the
stressor was imposed in relation to the effect of NK cells on the metastatic
66 ADER & COHEN
process, forced swimming decreased NK cell activity and resulted in a two

fold increase in lung metastases.
Effects of Stress on Humoral and Cell-Mediated Immunity

Unlike the measurement of hormone levels or nonspecific defense reactions
that can be gauged by sampling factors circulating in blood, urine, saliva, etc,
the assessment of immune responses, such as most of those described above in
thc context of disease susceptibility, requires that experimental subjects be
immunized. This additional variable adds layers of complexity to the charac
terization of the effects of behavioral and other interventions on immune
function and the mediation of these effects. In addition to the quality and
quantity of environmental stimulation and the temporal relationship between a

stressor and immunization, one must, for example, consider the nature as well
as the concentration of antigen and the "cascade" of immune events that
eventuate in the production of antibody or a cell-mediated inflammatory re
sponse. This complexity is reflected in much of the data describing the effects
of stressful stimulation on different aspects of immune function.
The relevance of the concentration of antigen used for immunization in
studies of stress has been noted in the past (Solomon et al 1974). In our view,
studies that address immune function per se use what might be described as
suprathreshold levels of antigenic stimulation--eoncentrations of antigen cal
culated to induce a "robust" primary and secondary response. To the extent
that behaviorally induced neuroendocrine changes are capable of modulating
immune responses, the use of high levels of antigenic stimulation are not
comparable to the levels of antigen exposure experienced by the organism
under natural conditions and could be counterproductive as a research strategy
designed to elaborate behaviorally induced alterations in immunocompetence.
For these reasons, Moynihan et al (1990a) studied the effects of a stressor
(electric shock) on the response to low-dose antigenic stimulation. An im
munizing dose of as little as 1 flg of the protein antigen keyhole limpet
hemacyanin (KLH) was insufficient to elicit a detectable primary response but
was sufficient to prime mice. When shock was administered for seven days
before and after immunization or only on one day, 24 hr after priming, mice
exposed to the stressor showed a depressed antibody response to challenge
with a second injection of 1 flg of KLH relative to control mice that were
simply placed into the shock apparatus or that remained unmanipulated. When
mice were challenged with a higher dose of KLH (5 flg) there were no group
differences. It is thus possible that concentrations of antigen that uncondition
ally elicit robust immune responses could mask the effects of behavioral
interventions.
For the most part, antibody production is suppressed by stressful stimula
tion. Although differential housing (frequently mislabeled as "crowding" or
"isolation") may not qualify as a stressor, the manner in which animals are
housed or a change in housing conditions is sufficient to influence primary
and/or secondary antibody responses to several different antigens (e.g.

Cunnick et al 19 91; Edwards & Dean 1977 ; Edwards et a1 1980; Glenn &
Becker 1969; Rabin et al 1987a,b; Rabin & Salvin 1987; Solomon 1969;
Vessey 1964). Antibody responses are also suppressed when submissive, in
truder, and attacked and defeated rats are subsequently immunized (Beden &
Brain 1982, 1984; Fauman 1987; Fleshner et a1198 9; Ito et aI1983). A recent
review of these data has been provided by Bohus & Koo1haas (19 91). Even the
odors emitted by mice subjected to stressful stimulation are sufficient to influ
ence antibody production in conspecific recipients. In one study (Zalcman et
al 1991 a,b), the antibody ref>ponse to SRBC waf> suppressed in mice placed
into an apparatus vacated by conspecifics that had been exposed to a presumed
stressor; in another study (Cocke et aI19 92), immunization with KLH follow
ing prolonged exposure to alarm signals emitted by conspecifics undergoing

concurrent stimulation enhanced antibody responses in the group-housed re
cipients.
Antibody responses are influenced by early separation experiences. In rats,
brief handling and separation from the mother increased both primary and
secondary antibody responses to flagellin, a bacterial antigen (Solomon et al
1968). In mice, early separations from the mother resulted in a decreased
anti-SRBC antibody response (Michaut et al 1981), and separation from the
mother and rearing environment influenced the antibody response of monkeys
to an antigenic challenge (e.g. Coe et a11985, 1988).
Okimura and his colleagues (Okimura & Nigo 1986; Okimura et al
1986b,c) found that serum antibody titers and the number of antibOdy-forming
splenic cells of mice were depressed if physical restraint (12 hr/day on two
consecutive days) was imposed after, but not before, immunization with
SRBC, aT-cell dependent antigen. Both adrenalectomy and chemical sympa
thectomy blocked the stressor-induced immunosuppression.The response to a
hapten (TNP) conjugated to a type 2 T cell-independent carrier (Ficoll) was
not influenced by restraint, but there was enhanced antibody production in
response to a type 1T cell-independent antigen (LPS). In this case, adrenalec
tomy, but not sympathectomy, blocked the enhanced response. The differen
tial sensitivity of type 1 and type 2 T cell-independent antigens, which activate
different populations of B cells, is of additional interest in relation to the
differential effects of conditioning on the response to these antigenic stimuli
(see N. Cohen et a1197 9; Schulze et al 1 988; Wayner et al 1978).
Both primary and secondary antibody responses are suppressed when rats
are subjected to inescapable electric shock stimulation daily beginning before
and continuing after immunization with KLH (Laudenslager et al 1988). Ro
tating mice after but not before immunization with SRBC also depressed the
immune response to SRBC (Esterling & Rabin 1987). In contrast, avoidance
conditioning depressed the antibody response to SRBC relative to yoked ani
mals that experienced unavoidable shock and an apparatus control group
(Mormede et al 1988). The degree to which rats could avoid or escape shock
68 ADER & COHEN
influenced the immune response, but not in the hypothesized direction. Zalc
man and his colleagues (1988) subjected mice to a single session of footshock
0, 24, 48, 72, or 95 hr after immunization with SRBC. Both the number of
antibody-forming cells and serum anti-SRBC antibody titers were depressed,
but only in mice subjected to the stressor 72 hr after immunization, suggesting
that there is a critical period for this acute stressor, at least, on antibody
production. Based on changes in norepinephrine activity within the central
nervous system that resulL from this same schedule of electric shock treatment
(Anisman et a1 1987; Zacharko & Anisman 1988), Zakman et al expected that
"controllability" would have influenced the immune response. There were,
however, no differences between mice that were and were not able to escape
the electric shock.
A seemingly innocuous form of stimulation with the immediate and long

term ability to influence antibody production is the handling of animals. Moy
nihan et al ( l 990b) found that antibody production in response to KLH was
attenuated in adult mice that were immunized after a 2-week period of daily
handling. Raymond et al (1986) found that, depending on strain, rats that were
simply handled during the neonatal period had suppressed antibody titers in
response to subsequent immunization with SRBC. In response to flageUin
administration, adult rats handled during infancy showed an enhanced anti
body response. In related research, Taylor & Ross (1989) found that neonatal
restraint (1 hr/day during the first 10 days of life) suppressed antibody re
sponses to immunization with pneumococcal polysaccharide in adult rats. In
adult animals, the same restraint imposed for 3 weeks followed by a 3-week
4
interval before immunization had no discernible effects. Moynihan and her
associates (Moynihan et al 1989) subjected mice to a different number of
intraperitoneal (ip) injections of saline or just handling during the 2-week
period before the animals were injected with antigen. Daily handling as well
as the repeated ip injections of saline attenuated the production of antibody in
response to KLH relative to a group of unmanipulated mice. Whether there
was an attenuated response in the manipulated animals or an exaggerated
response in thc unmanipulated animals cannot be determined. Whether the
difference is a reflection of conditioning processes also remains to be deter
mined. In either case, methodological questions arise about the control or
"resting" state of immunized animals.
With respect to cell-mediated immune responses, animals subjected to
stressors tend to show delayed skin graft rejection (Wistar & Hildemann 1960)
and suppressed DTH responses (Okimura et al 1986a). In a series of experi
ments by Blecha and his colleagues (1982a,b), restraint, heat, and cold, three
commonly used stressors, had different effects on two different cell-mediated
4
The limited data available suggest that an exploration of the long-tenn effects of early life
experiences on immune function would be a fruitful avenue of research (Ader 1983; O'Grady &
Hall 1991).
immune responses. Restraint imposed before sensitization or challenge sup

pressed the delayed cutaneous hypersensitivity response to SRBC. Exposure
to cold for two days af ter sensitization also depressed the DTH response,
whereas exposure to cold for eight days increased the DTH response. Heat
exposure invariably increased the hypersensitivity response. Contact hyper
sensitivity to dinitrofluorobenzene was increased by each of these stressors.
Further, adrenalectomy or treatment with metapyrone abrogated the stressor
induced suppression of DTH but had no effect on thc stressor-induced en
hancement of the contact sensitivity response. Again, the literature provides
little justification for generalizing from one stressor to another-or from one
aspect of immune function to another.
Another immunologically relevant reaction to stressors is a suppression of
macrophage function (Pavlidis & Chirigos 1980; Jiang et al 1990; Okimura et

a1 1986a; Qunidos et a1 1986 ; Z willing et aI 1 990), which may be mediated by
a stressor-induced depression of IFN product ion (Glascr et al 1 986 ;
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 1 990) and cold water exposure
(Jiang et al 1990); in the study by Sonnenfeld et al (1992), electric shock
suppressed IFN-gamma production and the expression of class II antigens
which could, in turn, influence antibody- and cell-mediated immunocompet
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; Rinner et a1 1992; Weiss et al 1989b).
T he diff er en t i al housing o f ro den t s r es ul t s in differen ces in
lymphoproliferative responses to mitogens, NK cell activity, and IL-2 produc
tion (Ghoneum et al 1 987; Jessop et al 1 988; Rabin et al 1987a,b; Rabin &
Salvin 1987), the direction and magnitude of the effects being determined by
species, strain, sex, and duration of housing. Other agonistic social interac
tions can also reliably influence the response to T and B cell mitogens, NK
cell activity, and IL-2 production in fish as well as rodents (Bohus & Koolhaas
199 1 ; Faisal et al 1989; Ghoneum et al 1988; Hardy et al 1990; Raab et al
1986). In addition to changes in antibody production, Cocke et al (1992) also
found reduced splenic NK cell cytotoxicity in mice exposed to the odors
emitted by footshocked conspecifics.
In general, the in vitro response of laboratory rodents to T cell mitogens in
splenic and/or peripheral blood lymphocytes decreases following relatively
acute exposure to a variety of stressors such as restraint, noise, and s wimming
(Jiang et al 1990; Monjan & Collector 1977; Rinner et al 1992; Zha et al
70 ADER & COHEN
1992), and as a result of separation experiences (Ackerman et al 1 988). The

effects of separation experiences from mothers or peers in several nonhuman
primate species can have long-lasting effects (Coe et al 1989 ; Friedman et al
199 1 ; Gust et a1 1992; Laudenslager et a1 1985, 1990). Increases and decreases
in lymphocyte proliferation have also been observed in handled animals, de
pending on the amount of handling and the age at which it is experienced
(Lown & Dutka 1987; Moynihan et al 1990b ; Rinner et al 1992). Similarly,
NK cell activity is frequently, but not invariably, depressed following acute
exposure to a variety of stressors (Aarstad et al 1983; Jiang et al 1990;
Moynihan et al 1990a; Okimura et al 1986a; Steplewski & Vogel 1986 ;
Steplewski et aI 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 ( 198 1) found that, with in
creasing intensities of electric shock over a period of 18 hr, there was a
corresponding decrease in the proliferation of peripheral blood lymphocytes in
response to PHA, even when the assay was based on a constant number of
cells to correct for the stressor-induced decrease in the total number of circu
lating lymphocytes. Less reliable effects were found in the response of splenic
lymphocytes, although Weiss et al ( 1989b), using the same paradigm, found a
significant suppression of lymphoproliferation of both splenic and blood lym
phocytes. Under these conditions, they also found a decline in IL-2 and inter
feron (IFN) production. Batuman et al ( 1990) obtained essentially the same
results varying the number of days of electric shock stimulation and measuring
the response to both Con A and PHA. The proliferative response to B cell
mitogens (pokeweed mitogen and LPS) was not influenced by the stressful
stimulation. These investigators also noted a decrease in the total number of
splenic and peripheral blood lymphocytes, particularly of CD8+ cells. In addi
tion, IL-2 production was diminished after as little as one day of exposure to
the 3-hr period of stimulation.
Lysle et al ( 1987) also found that a single session of approximately 1 hr of
stressful stimulation during which rats received 8 or 16 (but not 4) signaled
footshocks was sufficient to depress the proliferative response of splenic and
peripheral blood lymphocytes to Con A stimulation. After five days of stimu
lation, the response of spleen but not blood cells had recovered. Similar effects
were obtained by Cunnick et al ( 1988). Thus, whether one varies the intensity
of electric shock, the number of sessions of stimulation, or the number of
shocks per session, the magnitude of this form of stressful stimulation is
related to the magnitude of the changes in at least some measures of cellular
host defenses in some immune compartments. However, results obtained by
Livnat et al ( 1985) and Lysle et al ( 1990b) with electric shock and by Weiss et
al ( 1989b) with qualitative and quantitative differences in stressful stimulation
suggest t hat this relationship may not be linear .
The ability t o predict or control the effects o f stressful stimulation has

become a major focus of stress-related research and, as a result, the effects
obtained by Laudenslager et al ( 1 983) 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 1 988) of their inability to reproduce these effects. In
contrast to the effects on antibody production, however, Mormede and his
colleagues ( 1 988) 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 ( 1 983) indicated that inescapable but
not escapable shock suppressed splenic NK cell activity in rats. In another

preliminary study (Irwin & Custeau 1 989), however, signaled electric shock
resulted in a more pronounced suppression of NK cell activity than unsignaled
5
shock.
Electric shock stimulation also suppresses NK cell activity (Cunnick et al
1 9 8 8 ; Keller et al 1 98 8 ; Lysle et al 1 990a; Lysle & Maslonek 1 99 1 ; Shavit et
al 1 984; Weiss et aI 1 9 89b), the kinetics of which are strain dependent in mice
(Zalcman et al 1 99 1 a) . Shavit and his colleagues ( 1 984, 1 986) found that
intermittent electric shock stimulation, which induces an opioid-mediated an
algesia, also depresses NK cytotoxicity, whereas continuous shock, which
results in a nonopioid analgesia, has no such effect.
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
ated by a preferential effect on T cells. Conditioned suppression of
lymphoproliferative responses in rats and mice, for example, has been ob
served in response to T-cell mitogens but not (or less reliably) in response to
B-cell mitogens (Kusnecov et al 1 98 8 ; Lysle et al 1 990b, 1 99 1 ; Neveu et al
1986). Adoptive transfer experiments also suggest that conditioning may be
mediated by T cell changes (Gorczynski 1 987). Splenocytes from conditioned
or experimentally naive animals were transferred into (irradiated) naive or
conditioned animals that were or were not subsequently reexposed to the CS.
Studies o f stressor control i n human subjects (Sieber e t a l 1 99 1 ; Weisse e t al 1 990) yield

imilar contrasting effects.
72 ADER & COHEN
The observed increases or decreases in the antibody-forming cell response to

SRBC depended on the donor cells and the conditioning treatment experi
enced by the recipient. The separate transfer of enriched T and B cells into
naive or conditioned mice suggested that conditioning effects were attribut
able to the adoptively transferred T cells (Gorczynski 1991). The question of
whether conditioning can modulate the antibody response to different types of
T-cell independent antigens has not been resolved (N. Cohen et al 1979;
Schulze et al 1988; Wayner et al 1978).
Stressful stimulation also seems to have greater effects on T cell than on B
cell function (e.g. Batuman et a1 1990 ; Lysle et al 1990b ; Mormede et a1 1988;
Moynihan et al 1990b). Several investigators have demonstrated conditioned
and stressor-induced decreases in IL-2 production that might account for the
suppression of T cell proliferation (e.g. Batuman et al 1990 ; Ghoneum et al
1988; Hardy et al 1990; Kandil & Borysenko 1988; Weiss et al 1989b).
However, adding IL-2 to incubated lymphocytes did not normalize the
stressor-induced suppression of lymphoproliferation (Weiss et al 1989a) .
These investigators did find that electric shock decreased the expression of
IL-2 receptors on lymphocytes, suggesting that a compromised ability to re
spond to IL-2 may contribute to stressor-induced immunosuppression (and,
v ia neural and/or endocrine pathways, conditioned antibody- and/or cell-medi
ated immune responses, as well).
The in vitro T cell effects of behavioral interventions appear to be differen
tially expressed by splenic and blood lymphocytes in the case of both condi
tioning (Lysle et al 1990a ; Lysle & Maslonek 1991) and stressful stimulation
(Cunnick et al 1988; Keller et al 1983, 1988; Lysle et al 1987 ; Rinner et al
1992). This could reflect the trafficking of lymphocytes and a resulting differ
ence in the kinetics of the response in these two compartments (Cunnick ct al
1988; Lysle et al 1987) ; it could also relate to differences in the manner in
which splenic and peripheral blood lymphocytes were cultured. However, the
fact that there is noradrenergic innervation of the spleen (Felten et al 1987)
and that the stressor-induced suppression of splenic but not blood lymphocyte
proliferation is blocked by �-adrenergic antagonists (Cunnick et al 1990)
suggests the operation of different mediating mechanisms.
With respect to neuroendocrine influences, it is reasonable to hypothesize
that conditioned alterations of immunologic reactivity could be mediated by
conditioned ncuroendocrine changes, but data collccted thus far are inconsis
tent with the proposition that such effects are mediated simply by nonspecific,
stressor-induced changes in hormone levels. As reviewed elsewhere (Ader &
Cohen 1991), an extensive literature and other recent studies (e.g. Roudebush
& Bryant 1991) directly contradict or are inconsistent with predictions that
would follow from a "stress mediation" hypothesis of the effects of condition
ing or that conditioning effects are adrenal dependent. An elevation in
glucocorticoids is a common (and sometimes defining) characteristic of a
stress response, and exogenously administered glucocorticoids are generally
(but not uniformly) immunosuppressive (Munck & Guyre 199 1) . Nonetheless,

an endogenous elevation in adrenocortical steroids in response to different
stressors cannot be in voked to account for most of the stressor-induced
changes in immunocompetence .
In terms of antigen-specific immune responses, Okimura et al ( 1986b)
found that adrenalectomy blocked the suppression of antibody responses to
SRBC in rats that had been subjected to restraint, but adrenalectomy did not
influence the immunosuppressive effects of rotation (Esterling & Rabin 1987).
In studies using electric shock (Laudenslager et a1 1988; Mormede et aI 1988),
no relationship between corticosterone levels and suppressed antibody produc
tion in rats was seen. Blecha et al ( 1982b) found that adrenalectomy attenuated
the suppression of a DTH response in restrained mice but did not affect the
restraint-induced enhancement of contact hypersensitivity. With respect to

nonspecific reactions, electric shock in rats induced a lymphopenia that was
adrenal dependent (Keller et al 198 1); the stressor-induced suppression of
mitogen responsi veness, however, was unaffected by adrenalectomy (Keller et
al 1983). The suppressed lymphoproliferative response of splenic T lympho
cytes, in particular, has been shown consistently to be indcpcndent of stressor
induced adrenal activity (e.g. Lysle et al 1990b; Monjan & Collector 1977;
Mormede e t a1 1988; Rabin et aI 1 987a,b; Weiss et aI 1989b). The stressor-in
duced suppression of NK cell activity and IL-2 production are not blocked by
adrenalectomy (e.g. Weiss et aI 1989b).
Both conditioned and stressor-induced alterations of immune and nonspe
cific defense responses have been attributed to the actions of catecholamines .
Gorczynski & Holmes ( 1989), for example, reported that both chlorpromazine
and amitriptyline abolished conditioned immunosuppressive responses based
on the pairing of a gustatory stimulus with CY. Lysle et al ( 1992a) reported
that the p-adrenergic antagonist propranolol blocked the effects of conditioned
stressor effects on the development of adjuvant-induced arthritis; but propran
olol itself may be capable of attenuating inflammatory responses (Kaplan et al
1980) . Cunnick and her colleagues ( 1 990) found that propranolol and nadolol
(a p-adrenergic antagonist that does not cross the blood-brain barrier) blocked
the electric shock-induced suppression of splenic but not peripheral blood
lymphocytes to Con A stimulation. Propranolol also blocked attenuation of the
lymphoproliferative response of splenic lymphocytes to a CS previously
paired with electric shock (Luecken & Lysle 1992). Neither propranolol nor
nadolol influenced the conditioned suppression of B cell mitogenesis of pe
ripheral blood lymphocyte responses or IL-2 production, but both antagonists
attenuated the conditioned suppression of IFN-gamma. The peripherally act
ing p-adrenergic receptor antagonist also blocked the suppression of IFN
gamma production induced by electric shock stimulation (Sonnenfeld et al
1992) .
Using a different stressor (repeated exposure to cold), Carr et al ( 1 992)
described an enhancement of splenic antigen-specific antibody production
74 ADER & COHEN
and, at the same time, su ppre ssed or unaltered serum levels of im
munoglobulins. In this instance, phentolamine blocked the effects of cold
exposure and propranolol potentiated the effects of the stressor. While little is
known of the immunologic effects of catecholamines in vivo, it is relevant to
note that Zalcman et al ( 199 1a) were unable to detect any meaningful relation
ship between the depression of brain levels of norepinephrine and the suppres
sion of NK cell activity induced by one hour of uncontrollable electric shock
stimulation. It is evident that any involvement of catecholamines in the media
tion of stressor-induced alterations of immunity is determined by interactions
involving the nature of the immune response and the compartment in which it
is measured and the neurochemical concomitants of the adaptive responses
induced by the nature of the stressor.

Opioids acting within the central nervous system have also been implicated
in the mediation of conditioned and stressor (electric shock)-induced alter
ations of nonspecific defen se responses. Cunnick and her colleagues ( 1988)
found that naltrexone, an opioid receptor antagonist, blocked a shock-induced
suppression of splenic NK cell activity but did not obviate suppression of the
splenic lymphocyte respon se to T cell mitogen s. Lysle et al ( 1992b) found that
naloxone (in doses higher than those used by Cunnick et al) b locked the
conditioned suppression of NK cell activity and the depressed response to both
T and B cell mitogens. Although the association between an olfactory CS and
poly I:C was unaffected, subsequent enhancement of NK cell activity in re
sponse to reexposure to the CS also could be blocked by naltrexone (Solvason
et aI 1989). N-methylnaltrexone, a quaternary form of naltrexone that does not
cross the b lood-brain barrier, did not interfere with these conditioned re
sponses.
That the effects of stressful stimulation on NK cell activity may be medi
ated by centrally acting opioids is suggested by the observations that the
immunosuppression induced by electric shock was prevented by pretreatment
with naltrexone but not by the peripheral actions of N-methylnaltrexone, and
that a dose-dependent suppression of NK cell activity could be induced by
morphine (Shavit et aI 1984). However, Shavit et al ( 1 986) found that NK cell
activity was suppressed to the same extent following 4, 14, or 30 daily ses
sions of electric shock stimulation , whereas tolerance to the immunosuppress
ive effects of morphine developed after 14 sessions. Also, a stressor-induced
suppression of NK cell activity was observed in both morphine-naive and
morphine-tolerant rats. Thus, the suppression of NK cell activity in response
to morphine and to stressful stimulation is not mediated by precisely the same
mechanisms. Of related interest is the report that serum obtained from mice or
rats subjected to physical restraint (Zha et al 1992) and electric shock (Weiss
et al 1989a) contained one or more factors that could suppress the
lymphoproliferative response of peripheral b lood lymphocytes from un
manipulated animals. Neither adrenalectomy nor naltrexone treatment altered
this effect (Zha et al I992).
It may also be relevant that some studies have uncovered different changes
in mitogenesis and/or NK cell activity in animals subjected to avoidable or
unavoidable, escapable or inescapable, or signaled or unsignaled electric
shock (Irwin & Custeau 1 989; Mormede et a1 1 988; Shavit et aI 1 983), despite
the fact that each of these stressful situations would fit the criterion for an
opioid-mediated analgesia that might be expected to suppress NK cell activity.

Other studies (e.g. Cunnick et al 1 98 8 ; Keller et al 1 98 8 ; Odio et a1 1 987) have
noted a dissociation between the effects of the same stressor, electric shock
(albeit of different magnitudes, intensity, and duration), on NK cell and mito
gen responses, both of which have been observed to be blocked by naltrexone
treatment in one study (Lysle et al 1 992b). There is abundant evidence that
opioids, for which there are receptors on lymphocytes (Blalock 1 988), can
influence immune functions. It is not likely, however, that centrally acting
opioids are the sole mediator of either conditioned or stressor-induced alter
ations of immunocompetence.
The fact that some agonistic or antagonistic neurochemical or pharmaco
logic intervention can block or mimic the immunologic effects of reexposure
to a CS or stressful stimulation does not, in itself, constitute an explanation of
the behaviorally induced effects. It suggests only that such a pathway is one
(of perhaps several) means by which such an effect could occur. Indeed, the
complexity of the multiple communication channels between the brain and the
immune system provides any number of other pathways through which behav
iorally induced alterations in immunity could be mediated. It is beyond the
scope of this review, however, to detail these interactions (see Ader et al
1 99 1 a) ; nor, because of the paucity of behavioral data, should we speculate on
their role in the psychophysiologic regulation of immunity. These interactions
can, however, be summarized as follows.
Primary (thymus, bone marrow) and secondary (spleen, lymph nodes, gut
associated lymphoid tissues) lymphoid organs are innervated by the sympa
thetic nervous system (Felten & Felten 1 99 1 ), and lymphoid cells bear
receptors for many neuroendocrine and neurotransmitter signals that have
demonstrable immunomodulating effects (Blalock 1 992). Moreover, microg
lia cells of the central nervous system can produce cytokines (e.g. Carr 1 992;
Guillian et al 1 986). Conversely, lymphocytes can produce neuroendocrine
factors such as proopiomelanocortin-derived peptides (Blalock 1 988). Also,
cytokines produced by macrophages and activated lymphocytes are signal
molecules ("immunotransmitters") that can energize the hypothalamo-pitu
itary-adrenal axis (e.g. B esedovsky & del Rey 1 99 1 ). This network provides
the structural foundation for and (in combination, perhaps) the mediation of
various kinds of relevant observation: that lesioning or electric stimulation of
areas within the hypothalamus results in alterations in immune function
(Felten et aI 1 99 1 ), and peak antibody production is associated with changes in
the electrical activity within the hypothalamus (Besedovsky et al 1 977); that
hypophysectomy and changes in circulating levels of hormones and neuro-
76 ADER & COHEN
transmitters can influence immune responses (e.g. Berczi & Nagy 1 99 1 ; Ader
et al 1 990), and that immunologic reactions alter circulating levels of hor
mones and neurotransmitters (e.g. Besedovsky & del Rey 1 99 1 ) ; and that
behavioral manipulations (e.g. Pavlovian conditioning, stressful stimulation)
can, as described above, modulate antigen-specific and nonspecific immune
responses, that the physiological effects of products of an activated immune
system can be conditioned (Dyck et al 1 990), and that immunologic dys
regulations have behavioral consequences (Ader et aI 199 I b) .
W e cannot yet specify the mechanisms underlying the functional relation
ship between the nervous system and the immune system-mechanisms
illustrated by conditioned and stressor-induced modulations of different com
ponents of immunological defenses. In fact, for the most part we cannot yet
specify the functional significance of the neuroanatomic ai, neurochemical,
and neuroendocrine connections between the brain and the immune system.
Only in recent years, however, has the autonomy of the immune system been
seriously questioned. B ehavioral research has played a central and enabling
role in provoking studies of interactions between the central nervous system
and the immune system, and now represents only one of several lines of
research that provide converging support for an integrated approach to an
understanding of adaptive processes.
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 in different species under a variety of
cxperimental conditions. Similarly, stressful stimulation influences antigcn
specific as well as nonspecific reactions. Moreover, both conditioning and
stressful stimulation exert biologically meaningful effects in the sense that
they can alter the development and/or progression of what are presumed to be
immunologically mediated pathophysiologic processes. These are highly re
producible phenomena that illustrate a functional relationship between the
brain and the immune system. However, the extent to which one can general
ize from one stressor to another or from one parameter of immunologic reac
tivity to another is limited. Few generalizations are possible because the direc
tion and/or magnitude of the effects of conditioning and "stress" in modulating
immune responses clearly depend on the quality and quantity of the behavioral
interventions, the quality and quantity of antigenic stimulation, the temporal
relationship between behavioral and antigenic stimulation, the nature of the
immune response and the immune compartment in which it is measured, the
time of sampling, a variety of host factors (e.g. species, strain, age, sex), and
interactions among these several variables. It seems reasonable to assume that
the immunologic effects of behaviorally induced neural and endocrine re
sponses depend on (interact with) the concurrent immunologic events upon
which they are superimposed. Conversely, the efficacy of immunologic de

fense mechanisms seems to depend on the neuroendocrine environment on
which they are superimposed. We seek to determine when and what im
munologic (or neuroendocrine) responses could be affected by what neuroen
docrine (or immunologic) circumstances. We therefore need studies that pro
vide a parametric analysis of the stimulus conditions, the neuroendocrine
and/or immunologic state upon which they are superimposed, and the re
sponses that are being sampled.
The neural or neuroendocrine pathways involved in the behavioral alter
ation of immune responses are not yet known. Both conditioning and stressOf
induced effects have been hypo thesized to result from th e action of
adrenocortical steroids, opioids, and catecholamines, among others. Indeed, all
of these have been implicated in the mediation of some immunologic effects

observed under some experimental conditions. We assume that different con
ditioning and stressful environmental circumstances induce differen t constel
lations of neuroendocrine responses that constitute the milieu within which
ongoing immunologic reactions and the response to immunologic signals
occur. Based on the complexity of the network of connections and regulatory
feedback loops between the brain and the immune system, these processes
appear to involve both neural and endocrine signals to the immune system and
signals from the immune system that are received by the nervous system and
provoke further neural and endocrine adjustments. Considering the variety of
immunologic processes involved, it does not seem likely-or biologically
adaptive-that there would be any single mediator of the diverse effects of
either conditioning or stressful stimulation. It does not seem likely, however,
that the ultimate elaboration of the mechanisms underlying behaviorally in
duced alterations of immune function will have important clinical and thera
peutic implications.
ACKNOWLEDGMENTS
Preparation of this review was supported by a USPHS Research Scientist

Award (K05 MH-063 1 8) to R.A.
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ANNUAL

Robert Ader and Nicholas Cohen

Department of Psychiatry and Microbiology and Immunology, University of Rochester

KEYWORDS: psychoneuroimmuno!ogy, conditioning, stress

During the past 10-15 years, psychoneuroimmunology-the study of the in­

(b) that behavioral processes are capable of influencing immunologic reactiv-

effects of conditioning and stress in the modulation of immune function. There

CONDITIONED MODULATION OF IMMUNITY

Immune responses, like other physiological processes, can be modified by

Effects of Conditioning on Humoral and Cell-Mediated

HUMORAL IMMUNITY Current interest in conditioned changes in immunologic

animals received saccharin. A placebo-treated group was injected with vehicle

CELL-MEDIATED IMMUNITY The immunosuppressive effects ofCY can also be

Gorczynski et a1 1982; see also Lysle et aI 1988).

Effects of Conditioning on Nonimmunologically Specific

tumor cells and may be involved in preventing tumor metastasis.

cells obtained from mesenteric lymph nodes showed no effects of es reexpos­

In a recent study, Coussons et al (1992) paired exposure to a distinctive

Antigen as Unconditioned Stimulus

In behavioral terms, an antigen is an unconditioned stimulus for activation of

conditioncd immune responses as distinct from conditioned im­

Biologic Impact of Conditioned Changes in Immunity

munosuppressive drug (CY). The onset of autoimmune disease in the geneti­

Conditioning in Human Subjects

1896:45). The literature contains descriptions of several similar cases of what

show anticipatory immunosuppressive changes. Peripheral blood was obtained

In the present context, "stress" refers to any natural or experimentally con­

Effects o f Stress on Disease

(including immunologic responses) induced by specific forms of stressful

behaviorally induced perturbations in immune function can influence or medi­

process, forced swimming decreased NK cell activity and resulted in a two­

Effects of Stress on Humoral and Cell-Mediated Immunity

quantity of environmental stimulation and the temporal relationship between a

and/or secondary antibody responses to several different antigens (e.g.

ing prolonged exposure to alarm signals emitted by conspecifics undergoing

A seemingly innocuous form of stimulation with the immediate and long­

immune responses. Restraint imposed before sensitization or challenge sup­

macrophage function (Pavlidis & Chirigos 1980; Jiang et al 1990; Okimura et

Effects of Stress on Nonimmunologically Specific Reactions

1992), and as a result of separation experiences (Ackerman et al 1 988). The

The ability t o predict or control the effects o f stressful stimulation has

not escapable shock suppressed splenic NK cell activity in rats. In another

MEDIATION OF BEHAVIORALLY INDUCED IMMUNE

There are no definitive data on the mediation of behaviorally conditioned or

Studies o f stressor control i n human subjects (Sieber e t a l 1 99 1 ; Weisse e t al 1 990) yield

The observed increases or decreases in the antibody-forming cell response to

(but not uniformly) immunosuppressive (Munck & Guyre 199 1) . Nonetheless,

restraint-induced enhancement of contact hypersensitivity. With respect to

induced by the nature of the stressor.

opioid-mediated analgesia that might be expected to suppress NK cell activity.

The acquisition and extinction of the conditioned suppression or enhancement

which they are superimposed. Conversely, the efficacy of immunologic de­

of these have been implicated in the mediation of some immunologic effects

Preparation of this review was supported by a USPHS Research Scientist

Aarstad, H. 1., Gaudemack, G., SeljeJid, R. Ader, R. 1 9 8 3 , D e v e l o p mental psycho­

ditioned suppression of humoral immunity 25

cortical steroids in the conditioned sup­ B l a l o c k , J . E . , e d . 1 99 2 . Neumimmuno­

pression of plaque-fonning cell response Psychol ogical stress and susceptibility to

further studies on the prediction of experi­ ter, A. B . , Manuck, S. B . , Kaplan, J. R.

Behav. Immun. 3:223-33

H., Glaser, R., Sheridan, J. F. 1 9 9 1 . The

Pohajdak, B . , Dresel, K. M . , Grant, D. ance o f time o f stress application and type

Clure, H. M. 1 992. Removal from natal

During the past 10-15 years, psychoneuroimmunology-the study of the in

cells obtained from mesenteric lymph nodes showed no effects of es reexpos

conditioncd immune responses as distinct from conditioned im

munosuppressive drug (CY). The onset of autoimmune disease in the geneti

In the present context, "stress" refers to any natural or experimentally con

behaviorally induced perturbations in immune function can influence or medi

process, forced swimming decreased NK cell activity and resulted in a two

A seemingly innocuous form of stimulation with the immediate and long

immune responses. Restraint imposed before sensitization or challenge sup

which they are superimposed. Conversely, the efficacy of immunologic de

Aarstad, H. 1., Gaudemack, G., SeljeJid, R. Ader, R. 1 9 8 3 , D e v e l o p mental psycho

cortical steroids in the conditioned sup B l a l o c k , J . E . , e d . 1 99 2 . Neumimmuno

further studies on the prediction of experi ter, A. B . , Manuck, S. B . , Kaplan, J. R.

physiological, and immunological conse

Influence of conditioned psychological nociceptive effects and dependence on in

Roberts, D. W. 1 988. Behaviorally condi tioning of the NK cell response. Prog.