Medical Hypotheses (2000) 54(6), 969978

2000 Harcourt Publishers Ltd

doi: 10.1054/mehy.1999.0998, available online at http://www.idealibrary.com on

Transplantation
psychoneuroimmunology: building
hypotheses
M. M. Klapheke
University of Louisville Department of Psychiatry and Behavioral Sciences, Louisville, Kentucky, USA

Summary The research findings of psychoneuroimmunology have not yet been fully applied to the field of
transplantation psychiatry. Though much study has been devoted to the impact of psychiatric disease on the
immunosuppressed state and disease progression in HIV-related illness, little has yet been written on the immunology
implications of psychiatric disturbances in the immunosuppressed post-transplant patient. Utilizing Medline literature
searches to review relevant research data in psychoneuroimmunology and transplantation immunology, the author
formulates and examines four transplantation psychoneuroimmunology hypotheses involving the potential impact of
depression on post-transplant organ rejection, cancer, coronary artery disease, and infections. The author concludes
that though major questions remain, it appears reasonable to include the impact of depression, and possibly other
psychological states, among factors that may affect the net state of immunosuppression in transplant patients. 2000
Harcourt Publishers Ltd

INTRODUCTION
Psychoneuroimmunology research has made exciting
contributions to our understanding of the impact of psychiatric factors (depression, stress and anxiety, and maladaptive coping) on immune functions (14). Study has
been devoted to the impact of psychiatric symptoms and
illness on the immunosuppression and disease progression of HIV-related illness (46), but little attention has
been devoted to date on the application of our current
understanding of psychoneuroimmunology to posttransplantation patients receiving immunosuppression.
A review of the psychoneuroimmunology and transplantation immunology literatures quickly leads to an

Received 9 August 1999

Accepted 12 October 1999
Correspondence to: Martin M. Klapheke, MD, University of Louisville
Department of Psychiatry and Behavioral Sciences, 601 South Floyd Street,
Suite 210, Louisville, Kentucky 40202, USA. Phone: +1 502 852 5867;
Fax: +1 502 852 1934; E-mail: mklapheke@pol.net

appreciation of the complexity of multiple feedback loops

in the immune system, with frequent shifts in direction
and flow of biological processes, and seemingly contradictory concomitant immunosuppressive and immunoactivation effects. For example, Newport and Nemeroff (1)
hypothesize the acute phase response to stress associated
with depression may lead to immunoactivation via an
increase in secretion of cytokines, some of which in turn
stimulate corticotropin-releasing factor (CRF) secretion,
and thus lead to activation of the hypothalamic-pituitaryadrenal (HPA) axis, but CRF hypersecretion may in turn
lead to immunosuppressive effects, that is, a decrease in
lymphocyte proliferation responses to mitogens, and
decreased natural killer cell activity (NKA). Newport and
Nemeroff acknowledge this hypothesis is still likely an
oversimplification (1).
As a result of these immunologic complexities, an
attempt to formulate clinical, teaching, or research models regarding transplantation psychoneuroimmunology
proves extremely challenging. For example, if one wishes
to study the potential infectious disease consequences of
the immune effects of depression in post-transplant
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patients, one must take into consideration the need to

control for an enormous number of factors: specific organ
transplanted; type of immunosuppression regimen used;
degree of antigen matching between donor and recipient
(which may affect response to viral pathogens (7)); effect
of depression on health care behaviors/medical compliance; use of prophylactic antimicrobials; whether the
donor and/or recipient were infected with a certain
microorganism pre-transplant (seronegative recipients of
organs from seropositive donors have a greater than 50%
risk of developing symptomatic cytomegalovirus [CMV]
disease (8)); factors known to impact on immune functioning (age, general health status, caffeine, tobacco, alcohol, other drugs, medications, exercise, sleep, certain
medical illness, weight change, nutritional factors, and
diurnal variation (911)); and multiple other factors that
affect the risk of infectious diseases (8).
Recognizing an attempt at hypothesis building may
prove too simplistic, it is still of theoretical and potential
clinical value to proceed. In the following article, the
author utilizes existing research data in the fields of psychoneuroimmunology and transplantation immunology
to formulate and examine hypotheses about transplanatation psychoneuroimmunology, addressing the
potential impact of psychiatric illness (focusing on
depression) on organ rejection as well as post-transplant
immunosuppressant adverse effects including cancer,
graft coronary artery disease, and infections. Available
research data relevant to the hypotheses is presented, utilizing multiple Medline searches (1966early 1999
searches utilized combinations of the following terms:
post-transplantation, depression, transplanation rejection,
post-transplantation cancer, post-transplantation lymphoproliferative disorder, coronary artery disease,

Table 1

cytomegalovirus, EpsteinBarr virus, and post-transplantation infection).

BUILDING HYPOTHESIS #1
Since T-cells are the primary immune cell type involved
in acute organ rejection, and since depression is associated with a decrease in both number of T-cells and in
vitro T-cell proliferation response to mitogens, then
depression may not exacerbate organ rejection; indeed,
immune alterations associated with depression might
blunt organ rejection (see Table 1).
Background
Many factors play a role in the complex biological process
of organ rejection besides the number of HLA (human
leukocyte group A) antigen matches between donor and
recipient. Also, the number of rejection episodes will play
a role in yet further biological events; for example, a
patient experiencing recurrent or chronic rejection will
be exposed to increased immunosuppressive medications, often followed by chronic viral infections (8).
T-cells are the primary immune cell type involved in
acute organ rejection
Singer and Bach (12) detail processes related to acute
organ rejection, which primarily involves T-cells: as the
donor graft (antigen presenting cells) presents foreign,
allogeneic major histocompatibility complex (MHC) class I
and II antigens to the recipients T-cells, precursor helper
T-cells respond preferentially to the class II antigens and
proliferate and secrete cytokines. These cytokines, plus

Hypothesis # 1: Depression and acute organ rejection

# Helper T-cells

DEPRESSION

T-cell proliferation
# Suppressor/Cytotoxic T-cells

() Helper T-cell Proliferation

Cytokine Secretion

() Suppressor/Cytotoxic T-cell Proliferation

Acute Organ Rejection

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class I antigens, stimulate the precursor cytotoxic (killer)

T-cells, which in turn proliferate and acquire the killer
phenotype. The overall data are consistent with a requisite role for cytotoxic T cells in rejection of most types of
grafts, with an additional amplification or other role
(sometimes essential) for CD4+ helper T cells (p. 110) (12).
Depression is associated with a decrease in both
number of T-cells and in vitro T-cell proliferation
response to mitogens
Though depression has been associated with both
immunoactivation and immunosuppressive effects (1),
most psychoneuroimmunology studies have focused on
the potential clinical relevance of the immunosuppressive effects, which have included a decrease in T-cell
immunity. Kronfol (11) found reduced lymphocyte mitogenic activity in depressed patients, whereas after a series
of studies Schleifer and coworkers (1315) concluded
altered immune system measures may be associated with
subgroups of depressed patients, that is, severity of
depression was associated with a decrease in responses to
T-cell mitogens. In their meta-analysis of studies, Herbert
and Cohen (16) found alterations in cellular immunity in
depressed patients; for example, clinical depression was
reliably associated with decreased lymphocyte proliferative responses to mitogens. They also noted a decrease in
the total number of lymphocytes and numbers of subtypes, including NK, B, and T-cells as well as subtypes
helper T-cells and suppressor/cytotoxic T-cells (though
the latter number was vulnerable to the file drawer problem). The authors postulated possible mechanisms of the
altered immunity but also acknowledged the health
implications of the findings are still unknown.

971

Inventory scores suggested 49% of patients were at least

mildly depressed 04 months pre-transplant, with immediate improvement post-transplant and with only 11%
even mildly depressed at 5 years follow-up. Surprisingly,
rejection episodes were found to be not related to healthrelated quality of life measures.
Hillebrands and colleagues studied quality of life at 6
and 12 months following kidney transplantation (22) and
found that organ rejection had a significant negative
effect on Center for Epidemiological Studies Depression
Scale and Sickness Impact Profile scores. The authors also
found, Physical complaints related to the rejection
process or worse graft function, side effects of antirejection treatment, and being faced with a serious setback
may all have been responsible for the impaired quality of
life (pp. 12671268).
Studying heart transplant patients before and 1 year
post-transplant, Deshields and coworkers (23) utilized the
Beck Depression Inventory and the Beck Anxiety
Inventory and found a significant positive correlation
between depression and anxiety and the number of rejection episodes in the first six months post-transplant.
However, though the study found an association between
depression and anxiety and heart transplant rejection, the
authors noted the direction of the relationship could not
be specified and thus, the relevant cause and effect relationships are open for speculation (p. 67S). The authors
suggest, One implication is that depression and anxiety
scores reflect the psychological response to the physical
challenge imposed by rejection In contrast, there is
also the possibility that patients suffering from depression and anxiety are more vulnerable to rejection (p.
67S).
BUILDING HYPOTHESIS #2

Depression may not exacerbate organ rejection;

indeed, immune alterations associated with depression
might blunt organ rejection
What additional research findings to date are relevant to
this hypothesis? A South African study (17) of 20 kidney
recipients at a mean of approximately 4 to 5 years posttransplant revealed 20% of patients were depressed to
varying degrees. Two Japanese studies (18,19) of renal
transplant patients raised the concern that organ rejection
may lead to depression. Kober and colleagues studied
liver transplant recipients (20) and noted, Critical situations such as rejection episodes or viral infections are
characterized by a clear increase of anxiety and depression (p. 130), but they do not provide data on timing of
depressive symptoms relative to rejection or infection.
Fisher and coworkers studied quality of life in heart
transplant patients (21) and found that Beck Depression

2000 Harcourt Publishers Ltd

If depression is associated with decreased natural killer

cell activity (NKA), and if natural killer cells have a key
role in surveillance against neoplastic growth and are
cytotoxic against lymphoma cells and solid tumor cells,
then depression in immunosuppressed transplant
patients may be associated with a further increase in risk
from some cancers (see Table 2).
Background
Post-transplant immunosuppression carries an increased risk of certain forms of cancer. In a recent
update from the United Network for Organ Sharing (24),
it was noted that, Transplant recipients may have a
20 to 40 times greater risk of lymphoma and a 1,000
times greater risk of Kaposis sarcoma than the general
population (p. 1).

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Table 2

Hypothesis # 2: Depression and post-transplantation cancer

Number of NK cells
()
Depression

NK cell activity

() NK surveillance against neoplastic growth

() NK cytotoxicity against lymphoma & solid tumor cells

Cancer

Depression is associated with decreased natural killer

cell activity (NKA)
Though the results of all studies are not in agreement
(15), Herbert and Cohen concluded from their metaanalysis (16) of studies of depression and immunity that
depression was associated with both lowered NKA and a
decreased number of natural killer cells; they also noted
that decreased NKA has been related to certain diseases
such as progression of cancer, chronic viral infection, and
autoimmune diseases. Newport and Nemeroff (1) agree
that a decrease in NKA in depression is the one largely
consistent finding (p. 226) from depression and immunity studies and suggest that hypersecretion of corticotropin-releasing factor (CRF) occurs in depression and
leads to a decrease in NKA. Jung and Irwin (25) recently
reviewed the literature on NKA and cancer and present
their findings that depression and smoking cigarettes
interact to decrease NKA; compared with controls, only
depressed patients who smoked had a marked decrease
in NKA, whereas depressed nonsmokers showed no significant differences in NKA from controls.
Natural killer cells appear to have a key role in
surveillance against neoplastic growth and are
cytotoxic against lymphoma cells and solid tumor cells
Natural killer cells, which are a form of lymphocyte that
is usually large and granular, are important in the bodys
defense against viral illnesses and have a suggested vital
role in the surveillance against tumor growth; they are
cytotoxic against lymphoma and solid tumor cells (26,27).

Medical Hypotheses (2000) 54(6), 969978

Depression in immunosuppressed transplant patients

may be associated with a further increase in risks from
some cancers
What additional research data is relevant to this hypothesis? Though there are no specific studies of transplant
patients, the following studies do address issues involving
psychological distress, social support, cancer progression,
and immune alterations.
McGee and coworkers (28) provide a meta-analysis of
longitudinal prospective studies assessing depression and
the development of cancer, though methodological concerns abound, they found the overall association
(expressed as an odds ratio) between depression and cancer incidence using the MantelHaenzel method was
1.14, with 95% CI of 0.991.30 (p. 189), which was of borderline statistical significance.
Citing studies demonstrating a correlation between
NKA and degree of systemic tumor spread, Levy and colleagues (29) studied breast cancer patients and found a
significant amount of NKA variance in 61 patients with
stage I and II breast cancer could be explained by five
variables, which included the perception of high quality
emotional support from a spouse or significant other, perceived social support from their physician, and active
seeking of social support as a major coping strategy.
Indeed, the patients perception of the quality of emotional support from significant others was the most important predictor of NKA. The authors suggest perceived
emotional support may lead to a protective biological
buffer for stressed cancer patients via increased NKA
Though limited in available data, a follow-up (minimum

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of 5 years) study of these patients revealed that NKA

measured at 15 months follow-up predicted disease recurrence; also, lower overall psychological distress or negative mood scores (Profile of Mood States form, or POMS) at
15 months follow-up predicted a longer disease-free survival (among those who experienced recurrence), but better perceived baseline social support was only marginally
significantly linked with disease outcome, with better support predicting longer time to recurrence (30).
Fawzy and coworkers (31) studied the effects of a six
week structured psychiatric group intervention (education, stress management, enhancement of coping skills,
and support) on postsurgical patients with malignant
melanoma, and found a significant increase in the percent of NK cells plus an increase in NK cell cytotoxicity
augmentation by interferon (a measure of NK cell function). Consistent with these findings, Esterling and colleagues (9) found former and current caregivers of
patients with Alzheimers disease (considered together as
a chronically stressed group) had a significantly poorer
activation response of enriched NK cells to the cytokines
recombinant interferon- (rIFN-) or recombinant interleukin-2 (rIL-2) compared to controls; the authors data
was consistent with positive emotional and tangible
social support as a possible mediator, with higher
enriched NK cell responses associated with higher levels
of support. These authors also found that subjects higher
in Beck Depression Inventory-Short Form scores had
lower enriched NK cell cytotoxic responses to rIL-2 but
not to rIFN-; after controlling for contributions of
depression, the effects of heightened levels of positive
social support on enriched NK cell responses to the two
cytokines were unchanged.
Studies have suggested positive effects of psychosocial
interventions on prognosis in certain cancers (32,33).
Spiegel and colleagues (32) studied women with metastatic breast cancer randomized to either a control group or
an intervention group that received one year of weekly
supportive group therapy including self-hypnosis for
pain; though both groups received routine oncology care,
at ten year follow-up patients in the intervention group
survived significantly longer. Interestingly, a battery of
extensive psychological assessments before randomization did not significantly predict survival. However, the
authors do note that their treatment intervention did
significantly reduce anxiety, depression and pain. They
speculate on mechanisms that might account for the
increased survival in the intervention group, focusing on
social support, and also note, Neuroendocrine and
immune systems may be a major link between emotional
processes and cancer course (p. 891) (32).
Similarly, in a follow-up study of their patients with
malignant melanoma (see above) Fawzy and coworkers
(33) reported on the effects of their six week structured
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psychiatric group treatment on postsurgical patients with

malignant melanoma. Though the study validity is limited
by the small number of patients involved, the authors
found that patients in the group treatment intervention
had a statistically significant better survival rate than controls at follow-up 56 years after primary surgery. The
authors had previously shown (34) that as a whole, most
patients had high levels of psychological distress at baseline comparable with those of other types of patients
with cancer as well as patients suffering from AIDS or
undergoing bone marrow transplantation (p. 722) but
that at six months follow-up the treatment intervention
group had significantly lower depression, fatigue, confusion, and total mood disturbance, and were utilizing more
active behavioral and active cognitive coping than controls. Interestingly, in the 56 year follow-up study of these
patients (33), higher psychological distress at baseline
(which may be an important mobilizer of coping
resources (p. 688)) and higher baseline coping scores were
related to lower recurrence and death. Though changes in
POMS TMD (Profile of Mood States, with results summed
to obtain a Total Mood Disturbance score for affective
state) over the first six months did not show any relationship to outcome, an increase in active behavioral coping
scores was significantly related to better survival with a
similar trend apparent also for recurrence rates. Higher
baseline NKA was related to lower recurrence rates, and
the authors noted, Changes in the immune system via
neuro-endocrine processes may be a primary link between
psychological state and the course of cancer (p. 688) (33).
In a recent editorial, Kiecolt-Glaser and Glaser (35)
note the multifactorial links between psychological factors and cancer: depression and stress might have direct
effects on carcinogenesis through modifications in DNA
repair and apoptosis, as well as indirect effects, through
the poorer destruction or elimination of abnormal cells
by reduced NK cell activity (p. 1271).
BUILDING HYPOTHESIS #3
This hypothesis involves the impact of depression on
immunosuppression-induced metabolic changes, with a
focus on atherosclerosis: since depression is associated
with increased morbidity and mortality from coronary
artery disease, and since accelerated graft atherosclerosis
is a major cause of morbidity and mortality in heart transplant patients, then depression may exacerbate cardiac
risks in post-heart transplant patients (see Table 3).
Depression is associated with increased morbidity and
mortality from coronary artery disease
Glassman and Shapiro (36) provide an excellent review of
studies of depression and coronary artery disease, which
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Table 3

Hypothesis # 3: Depression and post-heart transplant coronary artery disease

Depression:

Coronary Artery Disease Morbidity and Mortality

+
Post-transplantation Immunosuppression:

Graft Atherosclerosis in Heart Transplant Patients

Coronary Artery Disease Morbidity & Mortality in Depressed Post-Heart Transplant Patients
demonstrate a relationship between depression and the
development of ischemic heart disease as well as an
increased mortality from cardiovascular disease in
depressed patients; for example, patients assessed as
depressed shortly after suffering a myocardial infarction
were 3.5 times more likely to die in the first 6 months
post-myocardial infarction. Glassman and Shapiro
describe possible mechanisms for this association: depressions associated changes in autonomic tone could lead to
increased post-myocardial infarction mortality; two studies have shown an increased propensity for platelet aggregation in depressed patients, which could lead to plaque,
occlusion, and myocardial infarction; and studies have
suggested lipid metabolism alterations in depressed
patients may increase the risk of vascular disease.

are faced not only with the increased morbidity and mortality from coronary artery disease associated with
depression but also the accelerated graft atherosclerosis
known to occur in this transplant setting.
BUILDING HYPOTHESIS #4
If depression is associated with decreased T- and B-cell
proliferative responses to mitogens and with decreased
NKA, and since immunosuppressant medication is associated with increased susceptibility to certain infections,
then depression may compound the risk of infectious disease in post-transplant immunosuppressed patients (see
Table 4).
Background

Accelerated graft atherosclerosis is a major cause of

morbidity and mortality in heart transplant patients
Though reported rates of occurrence of graft coronary
artery disease vary (3740), authors agree it is a major
cause of morbidity and mortality following heart transplantation. Possible factors associated with the accelerated graft atherosclerosis in heart transplant patients
include: CMV infection (8,41); anti-endothelial antibodies
(42); hyperlipidemia (43); and chronic immune injury to
the endothelium with rapid intimal proliferation and subsequent lipid deposition (39).
Depression may exacerbate cardiac risks in post-heart
transplant patients
Though no specific research evidence has been published, it appears depressed post-heart transplant patients

Medical Hypotheses (2000) 54(6), 969978

When considering issues associated with infection in the

immunosuppressed post-transplant patient, one must
consider many caveats such as those outlined above
(Introduction) concerning the interactions of multiple
biological processes. For example, if one hypothesizes
that depression in the immunosuppressed patient may
further increase susceptibility to certain infections such
as cytomegalovirus (CMV), one must also keep in mind
that CMV infection itself has immunosuppressant effects
and can lead to opportunistic superinfections (8), thus
complicating the clinical picture of causes and effects.
Also, certain infections can contribute to cancer formation: for example, hepatitis B or C to hepatocellular carcinoma, and EpsteinBarr virus (EBV) and CMV to
post-transplant lymphoproliferative disorder (8,44).
Further, infection can contribute to organ rejection, e.g.
acute and chronic organ rejection can be associated with

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Table 4

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Hypothesis # 4: Depression and infectious disease in post-transplant patients

Depression:

T- and B-cell proliferation, Number of NK cells, NK cell activity

+
Immunosuppression:

Susceptibility to Infections

Risk of Infectious Disease in Depressed Immunosuppressed Post-transplant Patients

CMV infection, with rejection leading in turn to increased

CMV viral replication (8). These interacting processes thus
link all four of the hypotheses presented in this paper.
Herpes virus infections (e.g., CMV, EBV, Herpes simplex Type-1 [HSV-1], and herpes simplex Type-2 [HSV-2]),
especially CMV infections, provide an appropriate focus
for discussion of post-transplant patients and infectious
disease. CMV has been described as the most important
pathogen affecting transplant patients, with a major
impact on patient morbidity (8). EBV infection/reactivation is also very important in this population because of
its part in the pathogenesis of post-transplant lymphoproliferative disorder, which can range from a benign polyclonal process to a malignant treatment-resistant
monoclonal lymphoma (8,44).
Depression is associated with decreased T- and B-cell
in vitro proliferative responses to mitogens and with
decreased NKA
In Herbert and Cohens meta-analysis of studies (16),
depression was found to be associated with several large
alterations in cellular immunity, including decreased proliferative responses of T- and B-cell lymphocytes to mitogens and lowered NKA.
Immunosuppressant medication is associated with
increased susceptibility to infections
Fishman and Rubin (8) identify infection as the most
common life-threatening complication of long-term
immunosuppressive therapy (p. 1741), with prevention or
effective treatment being a primary goal in organ transplantation.
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Depression may compound the risk of infectious

disease in post-transplant immunosuppressed patients
Is depression associated with activation of CMV infection
from latency? Following infection with CMV, an individual remains infected for life; after primary infection,
reactivation from latency appears to occur because of the
inability of cellular immunity to maintain the virus latent
in host cells (45), with virus-specific cytotoxic T-cells
being the key defense (8). Fishman and Rubin (8) describe
many factors in transplant patients associated with activation of CMV from latency, including therapy with antilymphocyte antibodies and cytotoxic drugs, allogeneic
reactions, and systemic infection and inflammation (pp.
17461747) (8). Since depression is associated with a
decrease in T-cell proliferative response to mitogens, it
might promote activation of CMV from latency. Also, it is
possible that depressions association with increased
acute phase proteins and increased cytokines including
IL-6 (4648) may promote CMV activation, since systemic inflammation accompanied by the release of proinflammatory cytokines can lead to CMV activation (8). In
their meta-analysis of studies of depression and immunity, Herbert and Cohen (16) found that depression was
associated with increased antibody titers to CMV and
HSV-1.
Is depression associated with CMV persistence and
spread (after activation from latency)? The immunosuppressants cyclosporine, tacrolimus, and corticosteroids
interfere with the transplant recipients immune response
to CMV and thereby allow CMV to spread (8). It seems
possible that depression, through negative effects on cellular immunity and a decrease in NKA, may promote
CMV persistence and diffusion.
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What additional research findings to date are relevant

to this hypothesis? The following studies provide data on
depression and herpes virus infections, but involve nontransplant patients.
In a study of 43 depressed patients and 46 controls,
Amsterdam and colleagues (49) found no serologic evidence that depression was associated with activation of
EBV infection or that EBV infection caused depression.
Maes and coworkers (50) studied immune variables,
including antibodies to CMV and EBV in 14 healthy controls as well as 36 depressed patients with minor depression (adjustment disorder and dysthymic disorder),
major depression, and melancholia. They reported significantly increased circulating serum levels of soluble interleukin-2 receptor (sIL-2R), a marker of T-cell activation, in
depressed individuals. However, they found no evidence
that depression is linked to EBV or CMV infection (p.
133). In a study of 98 Air Force personnel undergoing
medical evaluation due to seropositivity for HIV (95% of
whom did not have AIDS but, rather, were in earlier
stages of infection), Praus and colleagues (51) measured
CMV IgG, EBV viral capsid antigen (VCA) IgG, and EBV
early antigen (EA) IgG, as well as anxiety and depression
(respective Hamilton scores > 10 were defined as having
significant levels of anxiety or depression). The authors
found that, Serum viral titers to EpsteinBarr virus and
cytomegalovirus were not correlated with anxiety or
depression scores (p. 392). However, it must be noted that
the Amsterdam, Maes, and Praus studies involved crosssectional, one-time measures and did not follow patients
before and after depression or before and after CMV or
EBV viral antibody titer change.
There is some evidence, though mostly involving
stress rather than depression, that does suggest a relationship between psychological factors and CMV and
other herpes infections. Allen and Tilkian (52) studied
immune variables including EBV antibodies in 12
patients with previous diagnoses of depressed mood
and/or personality disorders, reported all 12 had serologic
evidence of a chronic or recrudescent EBV viremia, and
concluded EBV viremia may be causally related to
depression. Cappel and coworkers (53) studied humoral
and cell-mediated immunity evidence of HSV and CMV
infections and found an apparent association between
HSV infection and psychotic depression, though their
findings suggested an HSV infection or recurrence a few
days or weeks before the onset of the depression and did
not find a similar association for CMV. Kiecolt-Glaser and
coworkers (54) studied spousal caregivers of dementia
victims and found decrements in cellular immunity during follow-up, including higher EBV VCA antibody titers
compared to controls; though severity of depressive
symptoms or presence of syndromal depression were not
reliably related to subsequent immune function changes,
Medical Hypotheses (2000) 54(6), 969978

lower levels of social support at intake was associated

with poorer immune function at follow-up.
Kennedy and colleagues reviews (45,55) detail their
own findings of increases in antibody levels to latent EBV
associated with stress (medical school academic examinations) suggesting virus reactivation; examinations were
also associated with decreased T-cell response to mitogens and decreased number and function of NK cells
(55). Significant changes in antibody titers to HSV-1 were
also found during examinations, with the lowest titers
found at the time of students return from summer vacation, though Kennedy points out conflicting reports in
the research literature regarding psychological issues and
HSV-1 reactivation (45). These same researchers also
found lowered lymphocyte proliferative responses to two
mitogens in separated or divorced women compared to
married controls, as well as significantly lower percentages of T helper cells and NK cells, and higher antibody
titers to EBV VCA, in women who had experienced marital separation within a year of being studied. In the
matched comparison group of married women, the
authors found poorer marital quality related to greater
depression, poorer response to two mitogens, and higher
titers to EBV VCA (55). Finally, they reported a tenfold
increase in HSV-1 titers and a two-and-a-half fold
increase in EBV VCA antibody titers in separated or
divorced men compared to controls (55).
Kennedy (45) concludes her review on stress-related
increases in susceptibility to development of primary,
recurrent, or reactivation of herpes virus infections by
noting: Although the precise mechanism of virus reactivation is not well understood, it is believed that the cellular immune response is critical in maintaining virus
latency, and that virus reactivation may result from a suppressed cellular immune response due to psychological
stress Those who might be at a particularly high risk
for developing illness include individuals who are already
immunocompromised, such as the elderly, AIDS patients,
and patients receiving chemotherapy (p. 238) (45). It is
certainly reasonable to include post-transplant immunosuppressed patients in the latter category. Perhaps most
intriguing of all is Kennedys final citation of studies suggesting psychosocial therapeutic interventions, e.g., relaxation training, may reduce herpes virus reactivation (45).
CONCLUSIONS
Clinical hypotheses in transplantation psychoneuroimmunology must involve dynamic models that consider
multiple biological processes in constant flux. Solomon
has described the immune system as follows: Extremely
complex feedback loops interact with other complex
loops There are systems which are so complex and
so interrelated that the conditions of the whole are not
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predictable on the basis of its elements Disease may be

more complex than even a multifactorial model can adequately describe (p. 398) (56). Our understanding of how
psychiatric illness and therapeutic interventions influence immunology (for example, how they may impact on
the threshold of certain events) in transplant (and nontransplant) patients remains rudimentary. Much more
research is necessary to answer the questions posed by
the above hypotheses. Though major questions remain
about the effects of depression (and other psychological
factors) on post-transplant graft rejection, cancer, metabolic processes such as post-heart transplant graft atherosclerosis, and infections, it appears reasonable at present
to include the impact of depression among factors that
may affect the net state of immunosuppression in transplant patients.

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