Journal of Consulting and Clinical Psychology

2002, Vol. 70, No. 3, 537547

Copyright 2002 by the American Psychological Association, Inc.

0022-006X/02/$5.00 DOI: 10.1037//0022-006X.70.3.537

Psychoneuroimmunology:
Psychological Influences on Immune Function and Health
Janice K. Kiecolt-Glaser and Lynanne McGuire

Theodore F. Robles

Ohio State University College of Medicine

Ohio State University

Ronald Glaser
Ohio State University College of Medicine

This review focuses on human psychoneuroimmunology studies published in the past decade. Issues
discussed include the routes through which psychological factors influence immune function, how a
stressors duration may influence the changes observed, individual difference variables, the ability of
interventions to modulate immune function, and the health consequences of psychosocially mediated
immune dysregulation. The importance of negative affect and supportive personal relationships are
highlighted. Recent data suggest that immune dysregulation may be one core mechanism for a spectrum
of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, Type 2
diabetes, certain cancers, and frailty and functional decline; production of proinflammatory cytokines that
influence these and other conditions can be stimulated directly by negative emotions and indirectly by
prolonged infection.

Cacioppo, & Kiecolt-Glaser, 1996). For a highly readable discussion of basic immunological material and a broad overview of the
field, see Rabin (1999).

In 1964 George F. Solomon coined the term psychoimmunology

and published a landmark article: Emotions, Immunity, and Disease: A Speculative Theoretical Integration (Solomon & Moos,
1964). Despite the importance of this inaugural conceptual article,
only a handful of human studies appeared prior to the 1980s.
However, the subsequent explosive growth in both animal and
human studies has provided a much clearer picture of the ways in
which behavior and emotions modulate immune function. This
review focused on human psychoneuroimmunology (PNI) studies
published during the past decade, particularly those that addressed
the health consequences of psychosocially mediated immune
alterations.
Various aspects of behavioral influences on immune function
have been reviewed elsewhere (Glaser & Kiecolt-Glaser, 1994;
Herbert & Cohen, 1993; Kiecolt-Glaser, 1999; Kiecolt-Glaser &
Glaser, 1999b; Rabin, 1999; Schedlowski & Tewes, 1999; Uchino,

Duration of a Stressor:
Implications for Immune Function and Health
Laboratory Models (5 60 min)
Acute laboratory stressors that typically last a half hour or less
provoke transient immune changes (Brosschot et al., 1994;
Kiecolt-Glaser, Cacioppo, Malarkey, & Glaser, 1992; Mills, Dimsdale, Nelesen, & Dillon, 1996; Naliboff et al., 1995; Schedlowski,
Jacobs et al., 1993). Both brief and longer term stressors are
associated with declines in functional aspects of immunity; however, in contrast to the decrements in lymphocyte numbers associated with longer term naturalistic stressors (Uchino et al., 1996),
laboratory stressors appear to increase cell numbers in some lymphocyte subpopulations. Most immune parameters return to resting
levels within 1 hour after cessation of laboratory stressors
(Kiecolt-Glaser et al., 1992). One possible mechanism may be the
acute secretion of stress-responsive hormones, particularly catecholamines, which can alter a number of aspects of immune
function (Rabin, 1999).
Cardiovascular and catecholaminergic reactivity tend to covary
when assessed under the same conditions, and high reactivity
research participants demonstrated greater immunological change
than low reactivity participants (Cacioppo et al., 1995; KiecoltGlaser et al., 1992). Both the duration and intensity of psychological stressors (as indexed by cardiovascular changes) are related to
the breadth and magnitude of immune changes in laboratory studies (Benschop, Rodriguez-Feuerhahn, & Schedlowski, 1996). In

Janice K. Kiecolt-Glaser, Department of Psychiatry and Institute for

Behavioral Medicine Research, Ohio State University College of Medicine; Lynanne McGuire, Department of Psychiatry, Ohio State University
College of Medicine; Theodore F. Robles, Department of Psychology,
Ohio State University; Ronald Glaser, Department of Molecular Virology,
Immunology, and Medical Genetics, Institute for Behavioral Medicine
Research, and Comprehensive Cancer Center, Ohio State University College of Medicine.
Work on this article was supported in part by National Institutes of
Health Grants K02 MH01467, R37 MH42096, PO1 AG16321, P50
DE17811, MO1-RR-0034, and T32 MH18831.
Correspondence concerning this article should be addressed to Janice K.
Kiecolt-Glaser, Department of Psychiatry, Ohio State University College
of Medicine, 1670 Upham Drive, Columbus, Ohio 43210. E-mail:
[email protected]
537

538

KIECOLT-GLASER, MCGUIRE, ROBLES, AND GLASER

fact, the immunological changes observed following short-term

stressors are very similar to those described following epinephrine
injections (Schedlowski, Falk, et al., 1993) and likely reflect
transient alterations in lymphocyte migration from lymphoid organs and peripheral blood mediated through receptors on lymphocytes or through sympathetic nervous system (SNS) innervation of
lymphoid organs like the spleen (Ackerman, Bellinger, Felten, &
Felten, 1991). Thus, these transitory changes in the distribution of
cells in circulation in peripheral blood (a process called trafficking)
probably do not represent a real change in cell numbers.
Mouse models suggest the possibility of hyperreaction of at
least one aspect of immune function following short-duration
stressors; the augmentation of delayed-type hypersensitivity
(DTH) responses in the skin appears to be mediated through
glucocorticoid and epinephrine stress responses (Dhabhar & McEwen, 1999). One study suggested that this relationship may occur
in humans; socially inhibited individuals produced an increased
DTH skin response after experiencing a condition of high social
engagement, consistent with the hypothesis that social inhibition
may be related to physiologic hyperresponsiveness (Cole, Kemeny, Weitznam, Schoen, & Anton, 1999). It should be noted that
transient hyperresponsiveness of immune responses in the skin is
not necessarily positive, for example, contact allergies and rosacea
are maladaptive).

Short-Term or Acute Stressors

A 10-year series of prospective studies of medical students
responses to examinations showed transient changes in multiple
facets of the cellular immune response and its mediators (KiecoltGlaser, 1999); academic stress has also been widely used as a
model by other laboratories (Dobbin, Harth, McCain, Martin, &
Cousin, 1991; Marshall et al., 1998; Segerstrom, Taylor, Kemeny,
& Fahey, 1998). The importance of these immunological alterations for health is suggested by several studies. For example,
stress influenced medical students response to a series of three
hepatitis B (Hep B) vaccinations (Glaser et al., 1992); the students
who seroconverted (produced an antibody response to the vaccine)
after the first vaccination were significantly less stressed and less
anxious than those who did not seroconvert until after the second
inoculation. These data suggest that the immune response to a
vaccine (and, by implication, to pathogens) can be modulated by a
relatively mild stressful event in young, healthy adults.
The immune response plays an important role in the early stages
of wound healing, and exam stress also substantially delayed
wound repair. Wounds placed on the hard palate 3 days before a
major test healed an average of 40% more slowly than those made
in the same individuals during summer vacation, and interleukin1
(IL-1), an important immunological mediator, was also substantially lower during exams (Marucha, Kiecolt-Glaser, & Favagehi,
1998).
Taken together, these data suggest that academic stress (and
other relatively short-term, commonplace stressors) can provoke
changes in a variety of different immune activities, and these
changes can be consequential for health. Of importance, student
populations are experts at taking teststhey have long histories
of performing well under these very conditions. The fact that
something as transient, predictable, and relatively benign as exam

stress produces immune change suggests that other everyday stressors produce similar alterations.

Chronic Stress
The ability to unwind after stressful encounters (i.e., quicker
return to ones neuroendocrine baseline) influences the total burden that stressors place on an individual (Frankenhaeuser, 1986).
Stressors that are resistant to behavioral coping, particularly stressors perceived as unpredictable and uncontrollable, may continue
to be associated with elevated stress hormones even after repeated
exposure (Baum, Cohen, & Hall, 1993). For example, men and
women who provide long-term care for a spouse or parent with
Alzheimers disease typically report high levels of stress as they
attempt to cope with the family members problematic behaviors,
and this stressor has been associated with prolonged endocrine and
immune dysregulation, as well as with health changes, including
alterations in vaccine response and wound healing (Castle,
Wilkins, Heck, Tanzy, & Fahey, 1995; Irwin et al., 1991; KiecoltGlaser, Glaser, Gravenstein, Malarkey, & Sheridan, 1996; Malarkey et al., 1996; Mills, Yu, Ziegler, Patterson, & Grant, 1999;
Vedhara et al., 1999; Vitaliano et al., 1998). Moreover, these
changes may persist after caregiving ends (Esterling, KiecoltGlaser, Bodnar, & Glaser, 1994; Glaser, Kiecolt-Glaser, Malarkey,
& Sheridan, 1998).
Other chronic or longer term stressors associated with immune
alterations include burnout at work (Lerman et al., 1999), imprisonment in a prisoner of war camp (Dekaris et al., 1993), isolation
and exposure to hostile climate (Muller, Lugg, & Quinn, 1995),
living near a damaged nuclear reactor (Baum et al., 1993), job
strain (Kawakami et al., 1997), and unemployment (Arnetz et al.,
1991). In a study in which volunteers were inoculated with several
different strains of cold viruses, stressors that lasted a month or
more were the best predictors of developing colds (S. Cohen et al.,
1998). Immunological changes have also been documented for
weeks or months following such natural disasters as earthquakes
and hurricanes (Ironson et al., 1997; Solomon, Segerstrom, Grohr,
Kemeny, & Fahey, 1997). Prolonged intrusive ruminations following a trauma or disaster have been related to maladaptive psychological functioning and may provide one avenue for persistent
immune dysregulation (Baum et al., 1993). For example, intrusive
thoughts were associated with lower levels of natural killer (NK)
cell activity among victims of a hurricane (Ironson et al., 1997).
Intrusive thoughts may maintain higher levels of distress, as well
as stress-related immune change (La Via et al., 1996).

Psychological Modifiers
Negative affect has been associated with immunological dysregulation in studies that have spanned the gamut from clinical
depression and chronic stress to transient mood changes induced
by laboratory manipulations (Herbert & Cohen, 1993; KiecoltGlaser, Malarkey, Cacioppo, & Glaser, 1994). Findings from an
innovative daily diary study demonstrated that antibody to an
orally ingested antigen was higher in saliva on days when participants reported more positive moods and lower in saliva with more
negative moods (Stone et al., 1994). Similarly, negative mood over
the course of a day was associated with reduced NK cell lysis
among women, and positive mood moderated this association

SPECIAL ISSUE: PSYCHONEUROIMMUNOLOGY

(Valdimarsdottir & Bovbjerg, 1997). Among healthy older adults,

decreased positive mood partially mediated the association between the stressor of moving and reduced NK cell lysis (Lutgendorf, Vitaliano, Tripp-Reimer, Harvey, & Lubaroff, 1999). Individuals with greater right-prefrontal cortex activation had lower
levels of NK cell activity than individuals with greater left-frontal
activation, and greater right-prefrontal activation was associated
with greater decline in NK activity in response to stress (Davidson,
Coe, Dolski, & Donzella, 1999). These data are consistent with
evidence that left-prefrontal activation is associated with positive
emotions, whereas the experience and expression of negative emotions is associated with greater right-prefrontal activation (Davidson, Jackson, & Kalin, 2000). Indeed, negative affect has been
conceptualized as a key pathway for other psychological modifiers described later in the article, personal relationships and
personality.
The link between personal relationships and immune function is
one of the most robust findings in PNI (Uchino et al., 1996). For
example, higher NK cell activity and stronger proliferative responses of peripheral blood leukocytes to mitogen stimulation
were associated with higher social support in women whose husbands were being treated for urologic cancer than among those
with less support (Baron, Cutrona, Hicklin, Russell, & Lubaroff,
1990). Medical students who reported better social support
mounted a stronger immune response to a Hep B vaccine than did
those with less support (Glaser et al., 1992). Individuals with fewer
social ties were more susceptible to respiratory viruses (S. Cohen,
Doyle, Skoner, Rabin, & Gwaltney, 1997). Spousal caregivers of
dementia sufferers who reported lower levels of social support on
entry into a longitudinal study and who were most distressed by
dementia-related behaviors showed the greatest and most uniformly negative changes in immune function 1 year later (KiecoltGlaser, Dura, Speicher, Trask, & Glaser, 1991). Spousal caregivers
who demonstrated poorer augmentation of NK cell activity to two
cytokines reported lower levels of social support and described
less closeness in their important relationships than did caregivers
who showed greater NK augmentation (Esterling, Kiecolt-Glaser
et al., 1994). Data on maternal separation in nonhuman primates
provides strong supportive evidence from a well-characterized
animal model (Coe, 1993).
However, when close relationships are discordant, they can also
be associated with immune dysregulation. For example, pervasive
differences in endocrine and immune function were reliably
associated with hostile behaviors during marital conflict among
diverse samples that included newlyweds selected on the basis
of stringent mental and physical health criteria, as well as couples
married an average of 42 years (Kiecolt-Glaser et al., 1997;
Kiecolt-Glaser et al., 1993; Kiecolt-Glaser, Newton, et al., 1996;
Malarkey, Kiecolt-Glaser, Pearl, & Glaser, 1994; Mayne, OLeary,
McCrady, Contrada, & Labouvie, 1997). Thus, although supportive personal relationships are associated with better immune function (Uchino et al., 1996), close personal relationships that are
chronically abrasive or stressful may provoke persistent immune
dysregulation.
On the basis of findings for negative affect and social support,
aspects of personality or coping styles associated with negative
moods or social relationships might well demonstrate immunological correlates under certain circumstances. For example, personality and coping styles such as repression, rejection sensitivity,

539

attributional style, and sociability have been associated with altered leukocyte counts in peripheral blood and dysregulated cellular immune function (Segerstrom, 2000). Indeed, optimism was
associated with more positive moods, coping, and differences in
response to stress among law students in their 1st year of study,
and these differences appeared to mediate optimists better immune function (Segerstrom et al., 1998). Similarly, in a sample of
HIV-infected men, situational optimism about health outcomes
was linked to slower immune decline, later symptom onset, and
longer survival time among those with AIDS (Kemeny, 1994;
Reed, Kemeny, Taylor, & Visscher, 1999). Among healthy older
adults, a sense of coherence, an indicator of dispositional resilience, moderated the association between anticipation of moving
and reduced NK cell lysis; low sense of coherence was associated
with the poorest level of NK cell lysis (Lutgendorf, Vitaliano, et
al., 1999).
In another arena, high hostility individuals exhibited greater
increases in NK cell cytotoxity following self-disclosure than did
those who were low on hostility (Christensen et al., 1996), consistent with the authors hypothesis that persons high in cynical
hostility would find disclosure more threatening; no differences
between high- and low- hostility participants were observed in the
nondisclosure condition. The data are consistent with prior data
linking self-disclosure with heightened SNS activity (Christensen
et al., 1996), as well as with the increased NK cell activity that
follows short-term laboratory stressors (Kiecolt-Glaser et al.,
1992).
The study of individual differences in PNI is still in its infancy,
but the data are promising. As the data on personality and coping
suggest, differences in perceptions and reactions to the same event
can provoke different endocrine and immune responses. In fact,
neuroendocrine mechanisms may mediate the associations between personality and coping styles and immune function (Segerstrom, 2000).

Interventions
PNI intervention studies have used a number of diverse strategies including hypnosis, relaxation, exercise, classical conditioning, self-disclosure, exposure to a phobic stressor to enhance
perceived coping self-efficacy, and cognitive behavioral therapies
with a range of populations; earlier literature is reviewed elsewhere (Kiecolt-Glaser & Glaser, 1992). On the positive side,
intervention work with HIV-seropositive individuals and malignant melanoma patients has produced promising results. An intensive group intervention for malignant melanoma, described in
more detail in the Cancer section, had positive consequences for
mood, immune function, and survival (Fawzy et al., 1993). One
excellent series of studies demonstrated that 10-week cognitive
behavioral stress management (CBSM) and aerobic-exercisetraining programs both buffered distress responses and immune
alterations following notification of HIV seropositivity in asymptomatic men (Antoni, 1997; Schneiderman et al., 1994; Schneiderman, Antoni, Saab, & Ironson, 2001). The CBSM intervention also
had positive consequences for mood and immune function in
further studies with gay men whose disease had progressed to a
symptomatic stage (Lutgendorf et al., 1997, 1998), and such effects have been maintained 6 to 12 months following the interven-

540

KIECOLT-GLASER, MCGUIRE, ROBLES, AND GLASER

tion (Antoni et al., 2000). Changes in coping and social support

related to the intervention appeared to mediate the reductions in
distress. Additionally, neuroendocrine mediators of immune cell
function associated with the CBSM intervention have been demonstrated (Antoni et al., 2000; Schneiderman et al., 2001).
Several researchers reported immunological differences between research participants who disclosed traumatic or upsetting
events compared with those in a nondisclosure condition (Christensen et al., 1996; Esterling, Antoni, Fletcher, Margulies, &
Schneiderman, 1994; Petrie, Booth, Pennebaker, Davison, &
Thomas, 1995). In the typical paradigm, participants were randomly assigned to one of two groups: Half the participants wrote
about traumatic or troubling experiences for 20 min on 4 consecutive days, whereas the remainder wrote about trivial events and
experiences. Results have been interpreted as evidence for the link
between inhibition of strong emotions and the development of
physical disease (Petrie et al., 1995). The benefits of disclosurebased interventions may depend on the extent to which individuals
become emotionally and cognitively involved in the disclosure
process, reorganize the meaning of the traumatic event, and reduce
avoidance of the stressful topic (Esterling, Antoni, et al., 1994;
Lutgendorf, Antoni, Kumar, & Schneiderman, 1994).
Although classical conditioning of the immune response has
been demonstrated in a number of animal studies, parallel studies
with humans have been relative rarities. However, there are some
provocative data; for example, there may be classical conditioning
of immune suppression during chemotherapy (Bovbjerg et al.,
1990), an important arena for further research. Among women
receiving chemotherapy for ovarian cancer, proliferative responses
to T-cell mitogens from peripheral blood samples drawn in the
hospital just prior to the treatment showed immune suppression
compared with samples obtained at home several days earlier, even
after controlling for increased anxiety. Consistent with the interpretation of the process as conditioned immune suppression, patients also demonstrated an increase in conditioned nausea prior to
treatment as well. Data from healthy adults demonstrate small
increases in NK cell activity in response to neutral stimuli after
pairing with injections of epinephrine (Buske-Kirschbaum,
Kirschbaum, Stierle, Lehnert, & Hellhammer, 1992). In contrast,
an effort to condition allergic skin responses was unsuccessful
(Booth, Petrie, & Brook, 1995); further studies are needed to
determine whether the lack of conditioning effects are due to small
sample size, design of conditioning trials, or differences in conditionability among varying classes of immune variables.
Studies involving hypnotic interventions are suggestive that
individuals may be able to alter skin inflammation following
antigenic challenge (Zachariae, 2001). Use of the double arm
technique has provided some of the better controlled hypnotic
research. Investigators have used variations of this paradigm with
both immediate and delayed hypersensitivity reactions; in these
studies, participants were injected with the same antigen in both
arms, and suggestions were made that one arm would show certain
characteristic changes (e.g., wheal, erythema, itching, burning, and
swelling), whereas the other would not. Although a number of
prior studies using this methodology have shown positive findings
(Kiecolt-Glaser & Glaser, 1992), one very well-controlled study,
using a different antigen, found no effects (Locke et al., 1994).
Further research is required to resolve whether intervention effects
result from specific immune-related imagery and suggestions ver-

sus general effects of a relaxed state and to determine the importance of participant characteristics such as hypnotic susceptibility.
Why do some studies show effects but not others? What types of
interventions and contexts are most likely to influence immune
function? Some aspects of the immune response seem to be relatively insensitive to psychological stress (Herbert & Cohen, 1993);
therefore, small effect sizes make it difficult to show relationships.
Assays that assess the function or the performance of lymphocytes,
rather than simple lymphocyte percentages or counts, are more
likely to respond to psychological stress (Herbert & Cohen, 1993);
moreover, the former also have greater relevance for health.
Additionally, if an individuals immune system is functioning
satisfactorily, it may not be possible to enhance it above normal
levels; in fact, it might be undesirable to do so. More is not
necessarily better (e.g., an overactive immune system may lead to
autoimmune disease). In the absence of any age-, disease-, or
stress-related downward alterations in a study populations immune function, any intervention designed to enhance immune
function could fail because of homeostatic regulation. As an analogy, if ones blood pressure were 110/70, it might be difficult to
lower it further with a behavioral intervention, and it is questionable whether any concrete health benefits would accrue as a
consequence.
It seems reasonable to assume that, in general, the narrower the
scope of a behavioral intervention and the shorter its time course,
the smaller and less enduring the impact, either psychological or
immunological; a number of interventions have been brief, often
limited to single sessions using imagery and hypnosis. In addition,
longer follow-up periods are certainly desirable and may show
changes not visible earlier, and this is likely to be particularly
important for more intensive interventions (e.g., Fawzy et al.,
1993).
Distress and poorer personal relationships appear to be associated with the down-regulation of immunity across a number of
studies. Psychological or behavioral therapies are often targeted at
one or both of these dimensions, and the addition of immunological measures to therapy outcome studies could produce very
interesting results. Although studies to date suggest promising
immune-related intervention effects, much methodological and
dismantling work remains to be done to advance the current state
of knowledge about important client characteristics (e.g., health
status, stressors, age, hypnotic susceptibility), active and independent intervention components (e.g., relaxation/hypnosis,
cognitive behavioral strategies, social support, specific vs. nonspecific factors), intervention characteristics (duration, frequency,
individual vs. group), and client-intervention matching and mediating mechanisms (e.g., negative affect, neuroendocrine) for producing health-relevant alterations in immune function.

Health Consequences
A growing literature supports the hypothesis that psychosocial
factors have clinically significant relationships with immunerelated health outcomes, including infectious disease, cancer,
wound healing, autoimmune disease, and HIV. At the same time,
there is limited direct empirical evidence for immune pathways
responsible for these links, in part because of methodological
issues (e.g., timing of blood samples). As the field advances, and
new immunological technologies are developed, it is increasingly

SPECIAL ISSUE: PSYCHONEUROIMMUNOLOGY

clear that immune cell subpopulations perform specialized immunologic functions. Thus, future work should identify and examine
immune measures that are directly relevant to particular health
conditions. Of importance, PNI studies typically use a battery of in
vitro assays; in human studies, in vitro assays are generally limited
to peripheral blood samples, which may not reflect important
immunological processes occurring in lymphoid organs or other
regions, such as the skin (Glaser et al., 1999).

Infectious Disease
Infectious illnesses occur relatively infrequently in the general
population, with most adults reporting only a few illness episodes
a year. As a consequence, alterations in low base rates are difficult
to detect, particularly with the relatively small sample sizes necessitated by the time and expense inherent in PNI research. As an
alternative, to help demonstrate causal relationships between psychosocial stressors and the development of infectious illness, investigators have inoculated participants with a pathogen or a
vaccine. For example, four laboratories have demonstrated that
psychosocial factors can modulate the response to a Hep B vaccination (Glaser et al., 1992; Jabaaij et al., 1993; Marsland, Cohen,
Rabin, & Manuck, 2001; Petrie et al., 1995). In data from two
studies, spousal dementia caregivers were significantly less likely
to show a clinically significant response to influenza virus vaccine
than were noncaregivers (Kiecolt-Glaser, Glaser et al., 1996; Vedhara et al., 1999). Following vaccination, antibody titers to a
pneumococcal vaccine fell over a 6-month period in dementia
caregivers, whereas antibody titers were stable among former
caregivers whose spouse had died and noncaregivers (Glaser,
Sheridan, Malarkey, MacCallum, & Kiecolt-Glaser, 2000). Among
a population of girls who had no previous exposure to rubella
virus, those with higher negative affect and lower self-esteem were
more likely to have lower antibody titers to a rubella virus vaccine
at 10 weeks postvaccination (Morag, Morag, Reichenberg, Lerer,
& Yirmiya, 1999). Volunteers who reported more enduring interpersonal difficulties with family or friends were substantially more
likely to develop a cold following inoculation with a rhinovirus (S.
Cohen et al., 1998). Moreover, increased IL-6 production was
associated with greater self-reported and objective (mucus weight)
symptoms of infection with influenza A virus and may be one
mediator of the relationship between stress and symptoms of
infection (S. Cohen, Doyle, & Skoner, 1999).
Studies such as these in which participants are inoculated with
a pathogen or a vaccine provide researchers with a means of
controlling exposure and dosage; moreover, because immune function may be assessed prior to the infectious challenge, these studies
provide better data on causality than is possible with naturally
occurring infections. Because individuals who were more stressed
and more anxious showed a delay in the immune response to the
vaccine (or showed no response), these same individuals might
also be impaired in developing protective immunity to other pathogens; thus, they could be at greater risk for more severe illness.
Indeed, adults who show poorer responses to vaccines also experience higher rates of clinical illness (Burns & Goodwin, 1990).

Cancer
Research that has attempted to link psychosocial stressors with
tumor development or progression has faced many obvious diffi-

541

culties, including etiology, treatment effects, tumor type, and stage

of disease (Andersen, Kiecolt-Glaser, & Glaser, 1994; KiecoltGlaser & Glaser, 1999b). Cancer is composed of a heterogeneous
group of diseases with multiple etiologies (Andersen et al., 1994),
and immunological involvement varies across different cancers.
Those cancers that are induced by chemical carcinogens (e.g., lung
cancer) may be less influenced by psychological, behavioral, and
immunological factors than are cancers that are associated with a
virus such as EpsteinBarr Virus (EBV), which are immunogenic.
Suppression of cellular immunity is associated with higher incidence of certain types of tumors, particularly leukemias and lymphoproliferative diseases in transplantation patients and Kaposis
sarcoma and EBV-associated B-cell lymphoma in AIDS patients
(Herberman, 2001). Compelling evidence exists for the role of
other cells of the immune system, particularly NK cells, in resisting the progression and metastatic spread of tumors once they have
developed (Herberman, 2001). To establish clear links between
psychosocial factors and tumor development and progression, the
magnitude of immune dysregulation induced by behavioral and
psychological factors must exceed the immune dysregulation associated with the malignant disease processes and treatment. Stage
of disease can have profound effects on how patients feel, and
cancer treatments such as chemotherapy and radiation therapy are
associated with a number of side effects, including immunological
toxicity. Despite these problems, several lines of work appear
promising.
Substantial evidence has linked psychological stress with immune down-regulation, particularly alterations in NK cell activity
(for a review see Kiecolt-Glaser & Glaser, 1999b). A study of
breast cancer patients found that psychological stress predicted
lower NK cell lysis and NK responses to cytokine stimulation
(Andersen et al., 1998). However, although the immune system is
likely a primary defense against only a subset of malignancies
(many tumors are not recognized as foreign by the immune system
and thus do not stimulate an immune response), stress may also
enhance carcinogenesis through hormones, alterations in cellular
DNA repair mechanisms, and/or effects on apoptosis (KiecoltGlaser & Glaser, 1999b). For instance, psychological stress was
associated with higher blood levels of prostate-specific antigen, a
marker for the development of prostate cancer; the specific physiological mechanisms underlying this relationship have yet to be
identified (Stone, Mezzacappa, Donatone, & Gonder, 1999). These
studies, along with the finding that depression and smoking had
synergistic effects on reduced NK cell lysis (Jung & Irwin, 1999),
underscore the importance of psychological variables in cancer
risk assessments (Kiecolt-Glaser & Glaser, 1999c).
Fawzy et al. (1993) evaluated both the immediate and longer
term effects of a 6-week structured group intervention that consisted of health education, enhancement of problem-solving skills
regarding diagnosis, and stress management techniques. Among
malignant melanoma patients, noteworthy intervention effects included reduced psychological distress and significant immunological changes compared with controls. A 6-year follow-up of these
patients showed a trend toward greater recurrence, as well as
significantly higher mortality in the control group than in intervention patients (Fawzy et al., 1993). Although the data are still
quite limited, these studies and others suggest that psychological or
behavioral factors may influence the initiation and/or progression

542

KIECOLT-GLASER, MCGUIRE, ROBLES, AND GLASER

of cancer, at least in part, through psychosocial influences on

hormones and immune function.

Wound Healing
Stress impedes wound healing, as well as some of the key
immunological mediators in the early phases of wound repair, such
as the proinflammatory cytokines. In studies that assessed repair of
standardized wounds, the stress-related delays in healing ranged
from 24% to 40% and the effect sizes (using a squared simple
correlation as a measure of the proportion of variance in healing
time accounted for by stress) were between .30 and .74 (KiecoltGlaser, Page, Marucha, MacCallum, & Glaser, 1998); unquestionably, these effects are both statistically significant and clinically
meaningful. Further work suggested a possible mechanism: Psychological stress has measurable negative consequences for proinflammatory cytokine production in the local wound environment
(Glaser et al., 1999).
Indeed, the stress-related deficits in wound repair are consistent
with a number of studies that have shown that greater fear or
distress prior to surgery is associated with poorer outcomes, including longer hospital stays, more postoperative complications,
and higher rates of rehospitalization (Contrada, Leventhal, &
Anderson, 1994; Johnston & Vogele, 1993). Given the substantial
consequences of stress for wound repair, and immune changes
associated with distress, even relatively small alterations in anxiety
could have substantial clinical consequences, both directly through
physiological mechanisms and indirectly through increased pain
and decreased compliance (Kiecolt-Glaser et al., 1998).

Autoimmune Diseases
In autoimmune diseases, a hyperactive immune response produces problems because it is unable to discriminate self from
nonself and, as a consequence, attacks the bodys own tissues.
Suppression of the immune response is one treatment frequently
used, with selection of medications, such as steroids, which inhibit
various aspects of the immune response. Although there is ample
anecdotal evidence linking stress with both exacerbation and remission of symptoms, the processes likely show considerable
variability across the spectrum of autoimmune disorders and are
not well understood (Rabin, 1999).
For example, animal and human data suggest that stress may
play a role in the development and course of multiple sclerosis
(MS); thus, to assess the possibility that differences in subjective
and physiological responses to stress might underlie susceptibility
of MS patients to stress-related exacerbations, researchers in one
well-designed study compared patients and controls cytokine
responses with a laboratory stressor (Ackerman, Martino, Heyman,
Moyna, & Rabin, 1998). Although patients and controls stress
responses did not differ, the authors suggested that psychological
stress may enhance certain cellular immune responses that are
potentially harmful to MS patients. Similar results were found in
adolescents with and without asthma. Immune changes were observed during academic examination and laboratory stressors, but
they did not differ between asthmatics and controls, and lung
function did not decline in asthmatics during examination stress
(Kang, Coe, & McCarthy, 1996).

In contrast, researchers in another study successfully predicted

changes in rheumatoid arthritis disease states using a priori decision rules. Women with rheumatoid arthritis were followed for 12
weeks (Zautra et al., 1998); although T cell numbers, soluble IL-2
receptors, and clinicians ratings of disease activity increased
during a week of increased interpersonal stress, women who reported more positive spousal interaction patterns and less spouse
criticism or negativity did not show as large an increase in clinical
symptoms. In this context, it is interesting to note that perturbations in the communication between the immune system and the
brain have been hypothesized to produce inflammatory diseases
such as rheumatoid arthritis, as well as affective disorders like
major depression (Sternberg, Chrousos, Wilder, & Gold, 1992).

HIV
As described earlier, intervention work with HIV-seropositive
individuals has produced promising results. In addition, several
laboratories have attempted to relate psychological variables to
immunological change and disease progression in people infected
with HIV. More rapid disease progression has been associated with
greater concealment of homosexual identity (Cole, Kemeny, Taylor, Visscher, & Fahey, 1996) and more cumulative stressful life
events and less cumulative social support over a 5-year period
(Leserman et al., 1999). Among Black women co-infected with
HIV-1 and human papillomavirus (a viral indicator of cervical
cancer), greater pessimism was associated with reduced NK cell
lysis, indicating possible greater risk for future invasive cervical
cancer, a Centers for Disease Control and Prevention-classified
AIDS-defining disease (Byrnes et al., 1998). Alternatively, more
deliberate cognitive processing about the death of a close friend or
partner was associated with greater likelihood of finding positive
meaning in the loss, less rapid decline in CD4 cell levels, and
lower rates of AIDS-related mortality over a 9-year period in
HIV-seropositive men (Bower, Kemeny, Taylor, & Fahey, 1998).
Among men with AIDS, situational optimism about health outcomes was linked to slower decline of immune function, later
symptom onset, and longer survival time (Kemeny, 1994).
A number of additional studies have provided evidence of
psychosocial correlates, for example Kemeny and her colleagues
(Kemeny, 1994; Kemeny et al., 1995) compared men who had lost
one or more close friends to AIDS in the prior year with men who
had not. Higher levels of depressed mood were associated with
lower numbers of CD4 cells and increased expression of activation markers on lymphocytes in nonbereaved men, but not in
bereaved men, a pattern that replicated across two cohorts. She
suggested that higher depression scores may represent different
processes in the two groups (e.g., grief in the bereaved, depressed
mood in the nonbereaved), and the two processes may have different immunological correlates. In addition, men characterized by
chronic and severe depression over a 2-year period demonstrated a
sharper decline in CD4 cells than nondepressed men who were
matched on age and CD4 levels at baseline (Kemeny, 1994). It
should be noted that some researchers have found no ties between
depression and progression (Lyketsos et al., 1993); however, others have argued that possible reasons for null findings may be
related to heterogeneity of research populations on such key factors as disease stage, drug abuse history, gender, health behaviors,
and age (Goodkin et al., 1994).

SPECIAL ISSUE: PSYCHONEUROIMMUNOLOGY

How Do Psychological Factors Influence

Immune Function?
The endocrine system serves as one central gateway for psychological influences on health; stress and depression can provoke
the release of pituitary and adrenal hormones that have multiple
effects on immune function (Rabin, 1999). For example, social
stressors can substantially elevate key stress hormones, including
catecholamines and cortisol, and these hormones have multiple
immunomodulatory effects on immune function (Glaser &
Kiecolt-Glaser, 1994). In addition, distressed individuals are more
likely to have multiple health behaviors that put them at greater
risk, including poorer sleep, a greater propensity for alcohol and
drug abuse, poorer nutrition, and less exercise, and these health
behaviors have immunological and endocrinological consequences
(Kiecolt-Glaser & Glaser, 1988). For instance, deep sleep is the
normal stimulus for much of the release of growth hormone, a
hormone that enhances a number of aspects of immune function
(Veldhuis & Iranmanesch, 1996); thus, stressors that modify the
architecture of sleep may also lessen growth hormone secretion.
Moreover, even partial sleep loss 1 night results in elevated cortisol levels the next evening (Leproult, Copinschi, Buxton, &
Cauter, 1997).
Although the endocrine system and health behaviors are likely
the primary avenues whereby psychological factors influence immune function, there are other pathways, such as by means of
SNS-innervation of lymphoid organs like the spleen (Ackerman et
al., 1991). The endocrine system and SNS play central roles in the
concept of allostatic load, the cumulative long-term effects of
physiological responses to stress (McEwen, 1998). In this conceptualization, the neuroendocrine system and SNS are considered
primary mediators of allostatic processes, as they play central roles
in a variety of adaptive processes and deleterious physiological
outcomes. However, the strongest evidence implicating the neuroendocrine system and SNS as primary mediators in immune
change in humans comes from laboratory studies of acute stress.
Neuroendocrine and SNS mediation of immune changes related to
chronic stress may also exist; for instance, lymphocyte insensitivity to glucocorticoids resulting from chronically elevated cortisol
has been reported in Alzheimers caregivers (Bauer et al., 2000),
but such mediation has not been consistently demonstrated. Further work in this area is needed; these interactions are complex and
require careful attention to methodological refinements in both
endocrine and immune measures.
More broadly, recent evidence has implicated dysregulation of
proinflammatory cytokines, a marker of chronic inflammation, as
a central component across a range of diseases in older adults;
particular emphasis has been placed on IL-6. Depression and
distress enhance the production of proinflammatory cytokines,
including IL-6 (Dentino et al., 1999; Lutgendorf, Garand, et al.,
1999; Maes et al., 1995, 1999; Zhou, Kusnecov, Shurin, DePaoli,
& Rabin, 1993). In addition, negative emotions may also contribute indirectly to the immune dysregulation evidenced by proinflammatory cytokine overproduction; repeated, chronic, or
slow-resolving infections or wounds enhance secretion of proinflammatory cytokines, a process that can serve to further inhibit
certain aspects of immune responses (e.g., IL-2, an important
defense against infection), and thus may contribute to the immunodepression of aging (Catania et al., 1997). Certainly there is

543

excellent evidence that stress impedes the immune response to

infectious challenges, amplifying risks for contagion and
prolonged-illness episodes; distress also provokes substantial delays in wound healing and enhances the risk for wound infection
after injury (Rojas, Padgett, Sheridan, & Marucha, 2002).
Thus, negative emotions such as depression or anxiety can
directly affect the cells of the immune system and either up- or
down-regulate the secretion of proinflammatory cytokines. In addition, negative emotions may also contribute to prolonged or
chronic infections or to delayed wound healing, processes that
indirectly fuel proinflammatory cytokine production. These
changes are likely to be greatest, and to carry the highest health
risks, among the elderly, who already show age-related increases
in IL-6 production (H. J. Cohen, 2000). Indeed, inflammation has
recently been linked to a spectrum of conditions associated with
aging, including cardiovascular disease, osteoporosis, arthritis,
Type 2 diabetes, certain lymphoproliferative diseases or cancers
(including multiple myeloma, non-Hodgkins lymphoma, and
chronic lymphocytic leukemia), Alzheimers disease, and periodontal disease (Ershler & Keller, 2000). Chronic inflammation
has been suggested as one key biological mechanism that may fuel
declines in physical function, leading to frailty, disability, and,
ultimately, death (H. J. Cohen, Pieper, Harris, Rao, & Currie,
1997; Hamerman, 1999; Taaffe, Harris, Ferrucci, Rowe, & Seeman, 2000). For example, elevated serum IL-6 levels predicted
future disability in older adults(Ferrucci et al., 1999), a finding the
authors suggest may reflect the effects of the cytokine on muscle
atrophy, and/or to the pathophysiologic role played by the cytokine
in particular diseases. In fact, IL-6 may function as a global
marker of impending deterioration in health status in older adults
(Ferrucci et al., 1999, p. 645); even after the point at which risk
factors such as cholesterol, hypertension, and obesity predict
health deterioration less successfully among the very old, chronic
inflammation continues to be an important marker (Ferrucci et al.,
1999).

Future Directions
A well-functioning immune system is central to good health.
Maladaptive immunological alterations may influence the etiology, progression, and/or severity of a variety of disorders or
diseases; whereas infectious disease, certain cancers, wound healing, and autoimmune disease have been addressed in this brief
review, the potential range is much broader, from ulcers to atherosclerosis (Rabin, 1999). Given its centrality, it is not surprising
that conditions or processes that influence immune function can
have diverse consequences for health. The field of PNI holds rich
promise for helping to understand the interplay between psychological functioning and health.
Immune function declines with age, particularly functional aspects of the cellular immune response (Burns & Goodwin, 1990);
these age-related decrements are thought to be associated with the
greatly increased morbidity and mortality from infectious illness
(and perhaps cancer) in the elderly. Furthermore, older adults show
greater immunological impairments related to depression or stress
than younger adults (Kiecolt-Glaser & Glaser, 1999a). Thus, older
adults represent a particularly important population for PNI research and are likely to be a central focus in the future (KiecoltGlaser & Glaser, 2001).

KIECOLT-GLASER, MCGUIRE, ROBLES, AND GLASER

544

There are now sufficient data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to
actual health changes. Although changes related to infectious
disease and wound healing have provided the strongest evidence to
date, the clinical importance of immunological dysregulation is
highlighted by increased morbidity and mortality risks across
diverse conditions and diseases related to proinflammatory cytokines (Harris et al., 1999; Papanicolaou, Wilder, Manolagas, &
Chrousos, 1998). The PNI field has grown tremendously in the
past 2 decades, and the future appears quite promising.

References
Ackerman, K. D., Bellinger, D. L., Felten, S. Y., & Felten, D. L. (1991).
Ontogeny and senescence of noradrenergic innervation of the rodent
thymus and spleen. In R. Ader, D. L. Felten, & N. Cohen (Eds.),
Psychoneuroimmunology (2nd ed., pp. 72114). San Diego, CA: Academic Press.
Ackerman, K. D., Martino, M., Heyman, R., Moyna, N. M., & Rabin, B. S.
(1998). Stressor-induced alteration of cytokine production in multiple
sclerosis patients and controls. Psychosomatic Medicine, 60, 484 491.
Andersen, B. L., Farrar, W. B., Golden-Kreutz, D., Kutz, L. A., MacCallum, R., Courtney, E., & Glaser, R. (1998). Stress and immune responses
after surgical treatment for regional breast cancer. Journal of the National Cancer Institute, 90, 30 36.
Andersen, B. L., Kiecolt-Glaser, J. K., & Glaser, R. (1994). A biobehavioral model of cancer stress and disease course. American Psychologist, 49, 389 404.
Antoni, M. H. (1997). Cognitive-behavioral intervention for persons with
HIV. In J. L. Spira (Ed.), Group therapy for medically ill patients (pp.
5591). New York: Guilford Press.
Antoni, M. H., Cruess, D. G., Cruess, S., Lutgendorf, S. K., Kumar, M.,
Ironson, G., et al. (2000). Cognitive behaviorial stress management
intervention effects on anxiety, 24-hr urinary norepinephrine output, and
T-cytotoxic/suppressor cells over time among symptomatic HIVinfected gay men. Journal of Consulting and Clinical Psychology, 68,
31 45.
Arnetz, B. B., Brenner, S. O., Levi, L., Hjelm, R., Petterson, I. L.,
Wasserman, J., et al. (1991). Neuroendocrine and immunologic effects
of unemployment and job insecurity. Psychotherapy and Psychosomatics, 55, 76 80.
Baron, R. S., Cutrona, C. E., Hicklin, D., Russell, D. W., & Lubaroff,
D. M. (1990). Social support and immune function among spouses of
cancer patients. Journal of Personality and Social Psychology, 59,
344 352.
Bauer, M. E., Vedhara, K., Perks, P., Wilcock, G. K., Lightman, S. L., &
Shanks, N. (2000). Chronic stress in caregivers of dementia patients is
associated with reduced lymphocyte sensitivity to glucocorticoids. Journal of Neuroimmunology, 103, 84 92.
Baum, A., Cohen, L., & Hall, M. (1993). Control and intrusive memories
as possible determinants of chronic stress. Psychosomatic Medicine, 55,
274 286.
Benschop, R. J., Rodriguez-Feuerhahn, M., & Schedlowski, M. (1996).
Catecholamine-induced leukocytosis: Early observations, current research, and future directions. Brain, Behavior, and Immunity, 10, 7791.
Booth, R. J., Petrie, K. J., & Brook, R. J. (1995). Conditioning allergic skin
responses in humans: A controlled trial. Psychosomatic Medicine, 57,
492 495.
Bovbjerg, D. H., Redd, W. H., Maier, L. A., Holland, J. C., Lesko, L. M.,
Niedzwiecki, D., et al. (1990). Anticipatory immune suppression and
nausea in women receiving cyclic chemotherapy for ovarian cancer.
Journal of Consulting and Clinical Psychology, 58, 153157.
Bower, J. E., Kemeny, M. E., Taylor, S. E., & Fahey, J. L. (1998).

Cognitive processing, discovery of meaning, CD4 decline, and AIDSrelated mortality among bereaved HIV-seropositive men. Journal of
Consulting and Clinical Psychology, 66, 979 986.
Brosschot, J. F., Benschop, R. J., Godaert, G. L., Olff, M., De Smet, M.,
Heijnen, C. J., & Ballieux, R. E. (1994). Influence of life stress on
immunological reactivity to mild psychological stress. Psychosomatic
Medicine, 56, 216 224.
Burns, E. A., & Goodwin, J. S. (1990). Immunology and infectious disease.
In C. K. Cassel, D. E. Risenberg, L. B. Sorensen, & J. R. Walsh (Eds.),
Geriatric medicine (pp. 312329). New York: Springer-Verlag.
Buske-Kirschbaum, A., Kirschbaum, C., Stierle, H., Lehnert, H., & Hellhammer, D. (1992). Conditioned increase of natural killer cell activity
(NKCA) in humans. Psychosomatic Medicine, 54, 123132.
Byrnes, D. M., Antoni, M. H., Goodkin, K., Efantis-Potter, J., Asthana, D.,
Simon, T., et al. (1998). Stressful events, pessimism, natural killer cell
cytotoxicity, and cytotoxic/suppressor T cells in HIV black women at
risk for cervical cancer. Psychosomatic Medicine, 60, 714 722.
Cacioppo, J. T., Malarkey, W. B., Kiecolt-Glaser, J. K., Uchino, B. N.,
Sgoutas-Emch, S. A., Sheridan, J. F., et al. (1995). Heterogeneity in
neuroendocrine and immune responses to brief psychological stressors
as a function of autonomic cardiac activation. Psychosomatic Medicine, 57, 154 164.
Castle, S., Wilkins, S., Heck, E., Tanzy, K., & Fahey, J. (1995). Depression
in caregivers of demented patients is associated with altered immunity:
Impaired proliferative capacity, increased CD8, and a decline in lymphocytes with surface signal transduction molecules (CD38) and a
cytotoxicity marker (CD56 CD8). Clinical and Experimental Immunology, 101, 487 493.
Catania, A., Airaghi, L., Motta, P., Manfredi, M. G., Annoni, G., Pettenati,
C., et al. (1997). Cytokine antagonists in aged subjects and their relation
with cellular immunity. Journals of Gerontology: Biological Sciences
and Medical Sciences, 52A, B93-B97.
Christensen, A. J., Edwards, D. L., Wiebe, J. S., Benotsch, E. G., McKelvey, L., Andrews, M., & Lubaroff, D. M. (1996). Effect of verbal
self-disclosure on natural killer cell activity: Moderating influence of
cynical hostility. Psychosomatic Medicine, 58, 150 155.
Coe, C. L. (1993). Psychosocial factors and immunity in nonhuman primates: A review. Psychosomatic Medicine, 55, 298 308.
Cohen, H. J. (2000). Editorial: In search of the underlying mechanisms of
frailty. Journals of Gerontology: Biological Sciences and Medical Sciences, 55A, M706-M708.
Cohen, H. J., Pieper, C. F., Harris, T., Rao, K. M. K., & Currie, M. S.
(1997). The association of plasma IL-6 levels with functional disability
in community-dwelling elderly. Journals of Gerontology: Biological
Sciences and Medical Sciences, 52A, M201M208.
Cohen, S., Doyle, W. J., & Skoner, D. P. (1999). Psychological stress,
cytokine production, and severity of upper respiratory illness. Psychosomatic Medicine, 61, 175180.
Cohen, S., Doyle, W. J., Skoner, D. P., Rabin, B. S., & Gwaltney, J. M.
(1997). Social ties and susceptibility to the common cold. JAMA, 277,
1940 1944.
Cohen, S., Frank, E., Doyle, W. J., Skoner, D. P., Rabin, B. S., &
Gwaltney, J. M. (1998). Types of stressors that increase susceptibility to
the common cold in healthy adults. Health Psychology, 17, 214 223.
Cole, S. W., Kemeny, M., Taylor, S. E., Visscher, B., & Fahey, J. (1996).
Accelerated course of human immunodeficiency virus infection in gay
men who conceal their homosexual identity. Psychosomatic Medicine, 58, 219 231.
Cole, S. W., Kemeny, M. E., Weitznam, O. B., Schoen, M., & Anton, P. A.
(1999). Socially inhibited individuals show heightened DTH response
during intense social engagement. Brain, Behavior, and Immunity, 13,
187200.
Contrada, R. J., Leventhal, E. A., & Anderson, J. R. (1994). Psychological
preparation for surgery: Marshaling individual and social resources to

SPECIAL ISSUE: PSYCHONEUROIMMUNOLOGY

optimize self-regulation. In S. Maes, H. Leventhal, & M. Johnston
(Eds.), International review of health psychology (Vol. 3, pp. 219 266).
Chichester, England: Wiley.
Davidson, R. J., Coe, C. C., Dolski, I., & Donzella, B. (1999). Individual
differences in prefrontal activation asymmetry predict natural killer cell
activity at rest and in response to challenge. Brain, Behavior, and
Immunity, 13, 93108.
Davidson, R. J., Jackson, D. C., & Kalin, N. H. (2000). Emotion, plasticity,
context, and regulation: Perspectives from affective neuroscience. Psychological Bulletin, 126, 890 909.
Dekaris, D., Sabioncello, A., Mazuran, R., Rabatic, S., Svoboda-Beusan, I.,
Racunica, N. L., & Tomasic, J. (1993). Multiple changes of immunologic parameters in prisoners of war. JAMA, 270, 595599.
Dentino, A. N., Pieper, C. F., Rao, K. M. K., Currie, M. S., Harris, T.,
Blazer, D. G., & Cohen, H. J. (1999). Association of interleukin-6 and
other biologic variables with depression in older people living in the
community. Journal of the American Geriatrics Society, 47, 6 11.
Dhabhar, F. S., & McEwen, B. S. (1999). Enhancing versus suppressive
effects of stress hormones on skin immune function. Proceedings of the
National Academy of Sciences, USA, 96, 1059 1064.
Dobbin, J. P., Harth, M., McCain, G. A., Martin, R. A., & Cousin, K.
(1991). Cytokine production and lymphocyte transformation during
stress. Brain, Behavior, and Immunity, 5, 339 348.
Ershler, W., & Keller, E. (2000). Age-associated increased interleukin-6
gene expression, late-life diseases, and frailty. Annual Review of Medicine, 51, 245270.
Esterling, B. A., Antoni, M. H., Fletcher, M. A., Margulies, S., & Schneiderman, N. (1994). Emotional disclosure through writing or speaking
modulates latent EpsteinBarr virus antibody titers. Journal of Consulting and Clinical Psychology, 62, 130 140.
Esterling, B. A., Kiecolt-Glaser, J. K., Bodnar, J., & Glaser, R. (1994).
Chronic stress, social support, and persistent alterations in the natural
killer cell response to cytokines in older adults. Health Psychology, 13,
291299.
Fawzy, F. I., Fawzy, N. W., Hyun, C. S., Elashoff, R., Guthrie, D., Fahey,
J. L., & Morton, D. L. (1993). Malignant melanoma: Effects of an early
structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Archives of General Psychiatry, 50,
681 689.
Ferrucci, L., Harris, T., Guralnik, J., Tracy, R., Corti, M., Cohen, H., et al.
(1999). Serum IL-6 level and the development of disability in older
persons. Journal of the American Geriatrics Society, 47, 639 646.
Frankenhaeuser, M. (1986). A psychobiological framework for research on
human stress and coping. In M. H. Appley & R. Trumbull (Eds.),
Dynamics of stress: Physiological, psychological, and social perspectives (pp. 101116). New York: Plenum.
Glaser, R., & Kiecolt-Glaser, J. K. (Eds.). (1994). Handbook of human
stress and immunity. San Diego, CA: Academic Press.
Glaser, R., Kiecolt-Glaser, J. K., Bonneau, R. H., Malarkey, W., Kennedy,
S., & Hughes, J. (1992). Stress-induced modulation of the immune
response to recombinant hepatitis B vaccine. Psychosomatic Medicine, 54, 2229.
Glaser, R., Kiecolt-Glaser, J. K., Malarkey, W. B., & Sheridan, J. F.
(1998). The influence of psychological stress on the immune response to
vaccines. Annals of the New York Academy of Sciences, 840, 656 663.
Glaser, R., Kiecolt-Glaser, J. K., Marucha, P. T., MacCallum, R. C.,
Laskowski, B. F., & Malarkey, W. B. (1999). Stress-related changes in
proinflammatory cytokine production in wounds. Archives of General
Psychiatry, 56, 450 456.
Glaser, R., Sheridan, J. F., Malarkey, W. B., MacCallum, R. C., &
Kiecolt-Glaser, J. K. (2000). Chronic stress modulates the immune
response to a pneumococcal pneumonia vaccine. Psychosomatic Medicine, 62, 804 807.
Goodkin, K., Mulder, C. L., Blaney, N., Ironson, G., Kumar, M., &

545

Fletcher, M. A. (1994). Psychoneuroimmunology and human immunodeficiency virus type 1 infection revisited. Archives of General Psychiatry, 51, 246 247.
Hamerman, D. (1999). Toward an understanding of frailty. Annals of
Internal Medicine, 130(June 1), 945950.
Harris, T., Ferrucci, L., Tracy, R., Corti, M., Wacholder, S., Ettinger, W. J.,
et al. (1999). Associations of elevated interleukin-6 and C-reactive
protein levels with mortality in the elderly. American Journal of Medicine, 106(May), 506 512.
Herberman, R. B. (2001). Immunotherapy. In R. E. Lenhard Jr., R. T.
Osteen, & T. Gansler (Eds.), Clinical oncology (pp. 215223). Atlanta,
GA: American Cancer Society.
Herbert, T. B., & Cohen, S. (1993). Stress and immunity in humans: A
meta-analytic review. Psychosomatic Medicine, 55, 364 379.
Ironson, G., Wynings, C., Schneiderman, N., Baum, A., Rodriguez, M.,
Greenwood, D., et al. (1997). Posttraumatic stress symptoms, intrusive
thoughts, loss and immune function after Hurricane Andrew. Psychosomatic Medicine, 59, 128 141.
Irwin, M., Brown, M., Patterson, T., Hauger, R., Mascovich, A., & Grant,
I. (1991). Neuropeptide Y and natural killer cell activity: Findings in
depression and Alzheimer caregiver stress. FASEB Journal, 5, 3100
3107.
Jabaaij, P. M., Grosheide, P. M., Heijtink, R. A., Duivenvoorden, H. J.,
Ballieux, R. E., & Vingerhoets, A. J. J. M. (1993). Influence of perceived psychological stress and distress on antibody response to low
dose rDNA hepatitis B vaccine. Journal of Psychosomatic Research, 37,
361369.
Johnston, M., & Vogele, C. (1993). Benefits of psychological preparation
for surgery: A meta-analysis. Annals of Behavioral Medicine, 15, 245
256.
Jung, W., & Irwin, M. (1999). Reduction of natural killer cytotoxic activity
in major depression: Interaction between depression and cigarette smoking. Psychosomatic Medicine, 61, 263270.
Kang, D., Coe, C. C., & McCarthy, D. O. (1996). Academic examinations
significantly impact immune responses, but not lung function, in health
and well-managed asthmatic adolescents. Brain, Behavior, and Immunity, 10, 164 181.
Kawakami, N., Tanigawa, T., Araki, S., Nakata, A., Sakurai, S.,
Yokoyama, K., & Morita, Y. (1997). Effects of job strain on helperinducer (CD4CD29) and suppressor-inducer (CD4CD45RA) T cells
in Japanese blue-collar workers. Psychotherapy and Psychosomatics, 66,
192198.
Kemeny, M. E. (1994). Stressful events, psychological responses, and
progression of HIV infection. In R. Glaser & J. K. Kiecolt-Glaser (Eds.),
Handbook of human stress and immunity (pp. 245266). San Diego, CA:
Academic Press.
Kemeny, M. E., Weiner, H., Duran, R., Taylor, S. E., Visscher, B., &
Fahey, J. L. (1995). Immune system changes after the death of a partner
in HIV-positive gay men. Psychosomatic Medicine, 57, 547554.
Kiecolt-Glaser, J. K. (1999). Norman Cousins Memorial Lecture 1998.
Stress, personal relationships, and immune function: Health implications. Brain, Behavior, and Immunity, 13, 6172.
Kiecolt-Glaser, J. K., Cacioppo, J. T., Malarkey, W. B., & Glaser, R.
(1992). Acute psychological stressors and short-term immune changes:
What, why, for whom, and to what extent? Psychosomatic Medicine, 54,
680 685.
Kiecolt-Glaser, J. K., Dura, J. R., Speicher, C. E., Trask, O. J., & Glaser,
R. (1991). Spousal caregivers of dementia victims: Longitudinal changes
in immunity and health. Psychosomatic Medicine, 53, 345362.
Kiecolt-Glaser, J. K., & Glaser, R. (1988). Methodological issues in
behavioral immunology research with humans. Brain, Behavior, and
Immunity, 2, 6778.
Kiecolt-Glaser, J. K., & Glaser, R. (1992). Psychoneuroimmunology: Can

546

KIECOLT-GLASER, MCGUIRE, ROBLES, AND GLASER

psychological interventions modulate immunity? Journal of Consulting

and Clinical Psychology, 60, 569 575.
Kiecolt-Glaser, J. K., & Glaser, R. (1999a). Chronic stress and mortality
among older adults. JAMA, 282, 2259 2260.
Kiecolt-Glaser, J. K., & Glaser, R. (1999b). Psychoneuroimmunology and
cancer: Fact or fiction? European Journal of Cancer, 11, 16031607.
Kiecolt-Glaser, J. K., & Glaser, R. (1999c). Psychoneuroimmunology and
immunotoxicology: Implications for carcinogenesis. Psychosomatic
Medicine, 61, 271272.
Kiecolt-Glaser, J. K., & Glaser, R. (2001). Stress and immunity: Age
enhances the risks. Current Directions in Psychological Science, 10,
18 21.
Kiecolt-Glaser, J. K., Glaser, R., Cacioppo, J. T., MacCallum, R. C.,
Snydersmith, M., Kim, C., & Malarkey, W. B. (1997). Marital conflict
in older adults: Endocrinological and immunological correlates. Psychosomatic Medicine, 59, 339 349.
Kiecolt-Glaser, J. K., Glaser, R., Gravenstein, S., Malarkey, W. B., &
Sheridan, J. (1996). Chronic stress alters the immune response to influenza virus vaccine in older adults. Proceedings of the National Academy
of Sciences, USA, 93, 30433047.
Kiecolt-Glaser, J. K., Malarkey, W., Cacioppo, J. T., & Glaser, R. (1994).
Stressful personal relationships: Endocrine and immune function. In R.
Glaser & J. K. Kiecolt-Glaser (Eds.), Handbook of human stress and
immunity (pp. 321339). San Diego, CA: Academic Press.
Kiecolt-Glaser, J. K., Malarkey, W. B., Chee, M., Newton, T., Cacioppo,
J. T., Mao, H., & Glaser, R. (1993). Negative behavior during marital
conflict is associated with immunological down-regulation. Psychosomatic Medicine, 55, 395 409.
Kiecolt-Glaser, J. K., Newton, T., Cacioppo, J. T., MacCallum, R. C.,
Glaser, R., & Malarkey, W. B. (1996). Marital conflict and endocrine
function: Are men really more physiologically affected than women?
Journal of Consulting and Clinical Psychology, 64, 324 332.
Kiecolt-Glaser, J. K., Page, G. G., Marucha, P. T., MacCallum, R. C., &
Glaser, R. (1998). Psychological influences on surgical recovery: Perspectives from psychoneuroimmunology. American Psychologist, 53,
1209 1218.
La Via, M. F., Munno, I., Lydiard, R. B., Workman, E. W., Hubbard, J. R.,
Michel, Y., & Paulling, E. (1996). The influence of stress intrusion on
immunodepression in generalized anxiety disorder patients and controls.
Psychosomatic Medicine, 58, 138 142.
Leproult, R., Copinschi, G., Buxton, O., & Cauter, E. V. (1997). Sleep loss
results in an elevation of cortisol levels the next evening. Sleep, 20,
865 870.
Lerman, Y., Melamed, S., Shragin, Y., Kushnir, T., Rotgoltz, Y., Shirom,
A., & Aronson, M. (1999). Association between burnout at work and
leukocyte adhesiveness/aggression. Psychosomatic Medicine, 61, 828
833.
Leserman, J., Jackson, E. D., Petitto, J. M., Golden, R. N., Silva, S. G.,
Perkins, D. O., et al. (1999). Progression to AIDS: The effects of stress,
depressive symptoms, and social support. Psychosomatic Medicine, 61,
397 406.
Locke, S. E., Bernard, J. R., Zachariae, R., Francine, M., Tollins, K.,
Covino, N. A., & Danforth, D. (1994). Effect of hypnotic suggestion on
the delayed-type hypersensitivity response. Journal of the American
Medical Association, 272, 4752.
Lutgendorf, S. K., Antoni, M. H., Ironson, G., Klimas, N., McCabe, P.,
Cleven, K., et al. (1997). Cognitive behavioral stress management decreases dysphoric mood and herpes simplex virus-type 2 antibody titers
in symptomatic HIV-seropositive gay men. Journal of Consulting and
Clinical Psychology, 65, 31 43.
Lutgendorf, S. K., Antoni, M. H., Ironson, G., Starr, K., Costello, N.,
Zuckerman, M., et al. (1998). Changes in cognitive coping skills and
social support during cognitive behavioral stress management intervention and distress outcomes on symptomatic human immunodeficiency

virus (HIV)-seropositive gay men. Psychosomatic Medicine, 60, 204

214.
Lutgendorf, S. K., Antoni, M. H., Kumar, M., & Schneiderman, N. (1994).
Changes in cognitive coping strategies predict EBV-antibody titre
change following a stressor disclosure induction. Journal of Psychosomatic Research, 38, 6378.
Lutgendorf, S. K., Garand, L., Buckwalter, K. C., Reimer, T. T., Hong, S.,
& Lubaroff, D. M. (1999). Life stress, mood disturbance, and elevated
interleukin-6 in healthy older women. Journals of Gerontology: Biological Sciences and Medical Sciences, 54A, M434-M439.
Lutgendorf, S. K., Vitaliano, P. P., Tripp-Reimer, T., Harvey, J. H., &
Lubaroff, D. M. (1999). Sense of coherence moderates the relationship
between life stress and natural killer cell activity in healthy older adults.
Psychology and Aging, 14, 552563.
Lyketsos, C. G., Hoover, D. R., Guccione, M., Senterfitt, W., Dew, M. A.,
Resch, J., et al. (1993). Depressive symptoms as predictors of medical
outcomes in HIV infection. JAMA, 270, 25632567.
Maes, M., Bosmans, E., De Jongh, R., Kenis, G., Vandoolaeghe, E., &
Neels, H. (1995). Increased serum IL-6 and IL-1 receptor antagonist
concentrations in major depression and treatment resistant depression.
Cytokine, 9, 853 858.
Maes, M., Lin, A., Delmeire, L., Van Gastel, A., Kenis, G., De Jongh, R.,
& Bosmans, E. (1999). Elevated serum interleukin-6 (IL-6) and IL-6
receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biological Psychiatry, 45, 833 839.
Malarkey, W., Kiecolt-Glaser, J. K., Pearl, D., & Glaser, R. (1994). Hostile
behavior during marital conflict alters pituitary and adrenal hormones.
Psychosomatic Medicine, 56, 4151.
Malarkey, W. B., Wu, H., Cacioppo, J. T., Malarkey, K. L., Poehlmann,
K. M., Glaser, R., & Kiecolt-Glaser, J. K. (1996). Chronic stress down
regulates growth hormone gene expression in peripheral blood mononuclear cells of older adults. Endocrine, 5, 3339.
Marshall, G. D., Jr., Agarwal, S. K., Lloyd, C., Cohen, L., Henninger,
E. M., & Morris, G. J. (1998). Cytokine dysregulation associated with
exam stress in healthy medical students. Brain, Behavior, and Immunity, 12, 297307.
Marsland, A. L., Cohen, S., Rabin, B. S., & Manuck, S. B. (2001).
Associations between stress, trait negative affect, acute immune reactivity, and antibody response to hepatitis B injection in healthy young
adults. Health Psychology, 20, 4 11.
Marucha, P. T., Kiecolt-Glaser, J. K., & Favagehi, M. (1998). Mucosal
wound healing is impaired by examination stress. Psychosomatic Medicine, 60, 362365.
Mayne, T. J., OLeary, A., McCrady, B., Contrada, R., & Labouvie, E.
(1997). The differential effects of acute marital distress on emotional,
physiological and immune functions in maritally distressed men and
women. Psychology and Health, 12, 277288.
McEwen, B. S. (1998). Protective and damaging effects of stress mediators. New England Journal of Medicine, 338, 171179.
Mills, P. J., Dimsdale, J. E., Nelesen, R. A., & Dillon, E. (1996). Psychologic characteristics associated with acute stressor-induced leukocyte
subset redistribution. Journal of Psychosomatic Research, 40, 417 423.
Mills, P. J., Yu, H., Ziegler, M. G., Patterson, T. L., & Grant, I. (1999).
Vulnerable caregivers of patients with Alzheimers disease have a deficit
in circulating CD62L-T lymphocytes. Psychosomatic Medicine, 61,
168 174.
Morag, M., Morag, A., Reichenberg, A., Lerer, B., & Yirmiya, R. (1999).
Psychological variables as predictors of rubella antibody titers and
fatigueA prospective, double blind study. Journal of Psychiatric Research, 33, 389 395.
Muller, H. K., Lugg, D. J., & Quinn, D. (1995). Cell mediated immunity
in Antarctic wintering personnel: 1984 1992. Immunology and Cell
Biology, 73, 316 320.
Naliboff, B. D., Solomon, G. F., Gilmore, S. L., Fahey, J. L., Benton, D.,

SPECIAL ISSUE: PSYCHONEUROIMMUNOLOGY

& Pine, J. (1995). Rapid changes in cellular immunity following a
confrontational role-play stressor. Brain, Behavior, and Immunity, 9,
207219.
Papanicolaou, D. A., Wilder, R. L., Manolagas, S. C., & Chrousos, G. P.
(1998). The pathophysiologic roles of interleukin-6 in human disease.
Annals of Internal Medicine, 128, 127137.
Petrie, K. J., Booth, R. J., Pennebaker, J. W., Davison, K. P., & Thomas,
M. G. (1995). Disclosure of trauma and immune response to a hepatitis
B vaccination program. Journal of Consulting and Clinical Psychology, 63, 787792.
Rabin, B. S. (1999). Stress, immune function, and health: The connection.
New York: WileyLiss & Sons.
Reed, G. M., Kemeny, M. E., Taylor, S. E., & Visscher, B. R. (1999).
Negative HIV-specific expectancies and AIDS-related bereavement as
predictors of symptom onset in asymptomatic HIV-positive gay men.
Health Psychology, 18, 354 363.
Rojas, I., Padgett, D. A., Sheridan, J. F., & Marucha, P. T. (2002).
Stress-induced susceptibility to bacterial infection during cutaneous
wound healing. Brain, Behavior, and Immunity, 16, 78 84..
Schedlowski, M., Falk, A., Rohne, A., Wagner, T. O. F., Jacobs, R., Tewes,
U., & Schmidt, R. E. (1993). Catecholamines induce alterations of
distribution and activity of human natural killer (NK) cells. Journal of
Clinical Immunology, 13, 344 351.
Schedlowski, M., Jacobs, R., Stratmann, G., Richter, S., Hadicke, A.,
Tewes, U., et al. (1993). Changes of natural killer cells during acute
psychological stress. Journal of Clinical Immunology, 13, 119 126.
Schedlowski, M., & Tewes, U. (Eds.). (1999). Psychoneuroimmunology:
An interdisciplinary introduction. New York: Plenum.
Schneiderman, N., Antoni, M., Ironson, G., Klimas, N., LaPerriere, A.,
Kumar, M., et al. (1994). HIV-1, immunity, and behavior. In R. Glaser
& J. K. Kiecolt-Glaser (Eds.), Handbook of human stress and immunity
(pp. 267300). San Diego, CA: Academic Press.
Schneiderman, N., Antoni, M., Saab, P. G., & Ironson, G. (2001). Health
psychology: Psychosocial and biobehavioral aspects of chronic disease
management. Annual Review of Psychology, 52, 555580.
Segerstrom, S. C. (2000). Personality and the immune system: Models,
methods, and mechanisms. Annals of Behavioral Medicine, 22, 180
190.
Segerstrom, S. C., Taylor, S. E., Kemeny, M. E., & Fahey, J. L. (1998).
Optimism is associated with mood, coping, and immune change in
response to stress. Journal of Personality and Social Psychology, 74,
1646 1655.
Solomon, G. F., & Moos, R. H. (1964). Emotions, immunity, and disease:
A speculative theoretical integration. Archives of General Psychiatry, 11, 657 674.
Solomon, G. F., Segerstrom, S. C., Grohr, P., Kemeny, M., & Fahey, J.
(1997). Shaking up immunity: Psychological and immunologic changes
after a natural disaster. Psychosomatic Medicine, 59, 114 127.
Sternberg, E. M., Chrousos, G. P., Wilder, R. L., & Gold, P. W. (1992).

547

The stress response and the regulation of inflammatory disease. Annals

of Internal Medicine, 117, 854 866.
Stone, A. A., Mezzacappa, E. S., Donatone, B. A., & Gonder, M. (1999).
Psychosocial stress and social support are associated with prostatespecific antigen levels in men: Results from a community screening
program. Health Psychology, 18, 482 486.
Stone, A. A., Neale, J. M., Cox, D. S., Napoli, A., Valdimarsdottir, H., &
Kennedy-Moore, E. (1994). Daily events are associated with a secretory
immune response to an oral antigen in men. Health Psychology, 13,
440 446.
Taaffe, D. R., Harris, T. B., Ferrucci, L., Rowe, J., & Seeman, T. E. (2000).
Cross-sectional and prospective relationships of interleukin-6 and
C-reactive protein with physical performance in elderly persons:
MacArthur Studies of Successful Aging. Journals of Gerontology: Biological Sciences and Medical Sciences, 55A, M709-M715.
Uchino, B. N., Cacioppo, J. T., & Kiecolt-Glaser, J. K. (1996). The
relationship between social support and physiological processes: A
review with emphasis on underlying mechanisms. Psychological Bulletin, 119, 488 531.
Valdimarsdottir, H. B., & Bovbjerg, D. H. (1997). Positive and negative
mood: Association with natural killer cell activity. Psychology and
Health, 12, 319 327.
Vedhara, K., Cox, N. K. M., Wilcock, G. K., Perks, P., Hunt, M., Anderson, S., et al. (1999). Chronic stress in elderly carers of dementia patients
and antibody response to influenza vaccination. Lancet, 353, 627 631.
Veldhuis, J. D., & Iranmanesch, A. (1996). Physiological regulation of the
human growth hormone (GH)-insulin-like growth factor type I (IGF-I)
axis: Predominant impact of age, obesity, gonadal function, and sleep.
Sleep, 19, S221S224.
Vitaliano, P. P., Scanlan, J. M., Ochs, H. D., Syrjala, K., Siegler, I. C., &
Snyder, E. A. (1998). Psychosocial stress moderates the relationship of
cancer history with natural killer cell activity. Annals of Behavioral
Medicine, 20, 199 208.
Zachariae, R. (2001). Hypnosis and immunity. In R. Ader, D. L. Felten, &
N. Cohen (Eds.), Psychoneuroimmunology (3rd ed., pp. 133160). San
Diego: Academic Press.
Zautra, A. J., Hoffman, J. M., Matt, K. S., Yocum, D., Potter, P. T., Castro,
W. L., & Roth, S. (1998). An examination of individual differences in
the relationship between interpersonal stress and disease activity among
women with rheumatoid arthritis. Arthritis Care and Research, 11,
271279.
Zhou, D., Kusnecov, A. W., Shurin, M. R., DePaoli, M., & Rabin, B. S.
(1993). Exposure to physical and psychological stressors elevates
plasma interleukin 6: Relationship to the activation of hypothalamicpituitary-adrenal axis. Endocrinology, 133, 25232530.

Received January 7, 2001

Revision received April 23, 2001
Accepted October 15, 2001