Preexisting mild sleep disturbance as a vulnerability factor for inflammation-induced depressed mood: a human experimental study.

Sleep disturbance and depression are common, particularly in females, and sleep disturbance is a well-known risk factor for depression. Systemic inflammation has been suggested as a potential mechanism of this association. This study examined whether preexisting sleep disturbance acted as a vulnerability factor for depressed mood induced by an inflammatory challenge in healthy females vs males. In a randomized double-blind placebo-controlled design, volunteers aged 18-50 (N = 111; 67 females) were assigned to placebo or low-dose endotoxin. Before substance administration, sleep disturbance was assessed using the Pittsburgh Sleep Quality Index and dichotomized using median split (⩾ 3 vs < 3). Self-reported depressed mood (profile of mood states) and circulating proinflammatory cytokines (interleukin-6, tumor necrosis factor-α) were repeatedly assessed over 6 h. Among females, moderation of depressed mood by sleep disturbance was significant even after adjustment for covariates (X(2) = 12.73, df = 6, P < 0.05). There was a robust time-by-condition interaction in females with sleep disturbance (X(2) = 26.22, df = 6, P < 0.001), but not in females without sleep disturbance (X(2) = 8.65, df = 6, P = 0.19). Although cytokines increased equally in all females, the correlations between cytokines and depressed mood were significantly stronger in females with sleep disturbance. Among males, no moderating effect of sleep disturbance was observed. Inflammation-induced depressed mood was considerably more severe among females reporting mild sleep disturbance compared with those reporting no sleep disturbance, suggesting that even mild sleep disturbance may increase vulnerability for inflammation-induced depression in females. Furthermore, sleep disturbance appears to increase the vulnerability to depression by augmenting affective sensitivity to cytokines rather than by enhancing cytokine responses to inflammatory challenge in females.

The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer.

To examine relationships following adjuvant chemotherapy between circulating pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints in early stage breast cancer patients. 33 breast cancer patients who had completed initial treatment (surgery, ± radiation, 23 chemotherapy, 10 no chemotherapy) obtained resting (18)F-FDG PET/CT brain imaging at baseline and 1 year later. Pro-inflammatory cytokine markers (IL-1ra, sTNF-RII, CRP, and IL-6) and cognitive complaints were also assessed at both time points. At baseline, consistent correlations were seen between the left medial frontal and right inferior lateral anterior temporal cortices and inflammatory markers within the chemotherapy group, and not in the no chemotherapy group. After 1 year, correlations persisted in the medial frontal cortex and the temporal cortex, the latter shifting superiorly. Both of these regional correlations demonstrated the highest levels of significance when looking across the 1 year time frame (IL-1ra: peak voxel p < 0.0005; cluster size p < 0.0005, p = 0.001 after correction (medial prefrontal), p < 0.0005; cluster size p = 0.001, p = 0.029 corr. (anterior temporal), sTNF-RII: p < 0.0005; cluster size p = 0.001, p = 0.040 corr. (medial prefrontal)). Positive correlations were also seen within the chemotherapy group between baseline memory complaints and the medial frontal (p < 0.0005; cluster size p < 0.0005, p < 0.0005 corr.) and anterior temporal (p < 0.0005; cluster size p < 0.0005, p = 0.002 corr.) cortices at baseline and 1 year later. Metabolism in the medial prefrontal cortex and anterior temporal cortex was found to correlate with both memory complaints and cytokine marker levels in chemotherapy patients.

A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity.

BACKGROUND: This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms. METHODS: Thirty-nine family dementia caregivers (mean age 60.3 years old (SD = 10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 min per day for 8 weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre-intervention and post-intervention. RESULTS: The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared with the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale compared with 31.2% and 19%, respectively, in the relaxation group (p < 0.05). The meditation group showed 43% improvement in telomerase activity compared with 3.7% in the relaxation group (p = 0.05). CONCLUSION: This pilot study found that brief daily meditation practices by family dementia caregivers can lead to improved mental and cognitive functioning and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample.

Does tumor necrosis factor-alpha (TNF-α) play a role in post-chemotherapy cerebral dysfunction?

Post-chemotherapy treated cancer patients frequently report cognitive difficulties. The biology of this phenomenon is poorly understood, with uncertainty about possible direct toxic effects on the brain, secondary effects from systemic inflammation, host factors/genetic predisposition to cognitive complaints, or hormonal changes influencing cognitive function. To elucidate possible mechanisms associated with post-treatment cognitive dysfunction among breast cancer survivors, in 2007 we established a prospective, longitudinal, observational cohort study of early stage breast cancer patients, recruited at the end of initial treatments (primary treatment exposure included surgery, ± radiation, ± chemotherapy), and prior to the initiation of adjuvant endocrine therapy. We assessed cognitive complaints, neuropsychological (NP) test performance, markers of inflammation, and brain imaging at baseline, 6 months and 12 months after enrollment. In this analysis of data from the first 93 patients enrolled in the cohort study, we focus on the relationship of circulating levels of proinflammatory cytokines to cerebral functioning and chemotherapy exposure. Among the proinflammatory cytokines tested (IL-1 ra, sTNF-RII, CRP, and IL-6) at baseline, only sTNF-RII was increased among chemotherapy exposed patients, with a significant decline in the year after treatment (p=0.003). Higher baseline sTNF-RII in chemotherapy patients was significantly associated with increased memory complaints. In chemotherapy exposed patients, the longitudinal decline in sTNF-RII was significantly correlated with fewer memory complaints over 12 months (r=-0.34, p=0.04). Higher baseline sTNF-RII was also associated with relatively diminished brain metabolism in the inferior frontal cortex (r=-0.55, p=0.02), as well as relatively increased inferior frontal metabolism after 1 year, in chemotherapy-exposed subjects. These preliminary findings suggest that post-chemotherapy increases in TNF-α may be playing an important role in the manifestations of cognitive complaints in breast cancer survivors.

Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II prospective cohort study.

BACKGROUND: Although basic research on neuroimmune interactions suggests that inflammatory processes may play a role in the development of fatigue, population-based evidence on this association is limited. This study examined whether plasma C-reactive protein (CRP) and interleukin-6 (IL-6), biomarkers of systemic inflammation, predict fatigue onset. METHOD: The Whitehall II study is a large-scale cohort study conducted in 20 civil service departments in London. Plasma CRP and IL-6 were measured in 4847 non-fatigued participants at phase 3 (1991-1993, aged 39-63 years). Fatigue was assessed using the Vitality subscale of the 36-item Short Form Health Survey (SF-36) at phase 3 and phase 4 (1995-1996). RESULTS: During a mean follow-up of 3.1 years, 957 new fatigue cases (19.7%) were identified using the pre-established cut-off score of ≤ 50 on the Vitality subscale. CRP values were dichotomized as low (<1.0 mg/l ) or high (≥ 1.0 mg/l) using the Centers for Disease Control/American Heart Association recommendations. Similarly, IL-6 values were also dichotomized as low (<1.5 pg/ml) or high (≥ 1.5 pg/ml). After full adjustment for sociodemographic and biobehavioral covariates, the odds ratios for new-onset fatigue were 1.28 [95% confidence interval (CI) 1.09-1.49, p = 0.003] for high CRP and 1.24 (95% CI 1.06-1.45, p = 0.008) for high IL-6. Similar results were found when CRP and IL-6 were treated as continuous variables. CONCLUSIONS: Plasma CRP and IL-6 were prospectively associated with new-onset fatigue, supporting the hypothesis that low-grade inflammation has a role in the development of fatigue.

Sleep depth and fatigue: role of cellular inflammatory activation.

Individuals with underlying inflammation present with a high prevalence of non-specific co-morbid symptoms including sleep disturbance and fatigue. However, the association between cellular expression of proinflammatory cytokines, alterations of sleep depth and daytime fatigue has not been concurrently examined. In healthy adults (24-61 years old), evening levels of monocyte intracellular proinflammatory cytokine production were assessed prior to evaluation of polysomnographic sleep and measures of fatigue the following day. Stimulated monocyte production of interleukin-6 (IL-6), but not tumor necrosis factor α (TNF-α), was negatively associated with slow wave sleep (ΔR²=.17, p=.029). In contrast, stimulated monocyte production of IL-6 was positively associated with rapid-eye movement (REM) sleep duration during the first sleep cycle (ΔR²=.26, p<.01). Moreover, evening stimulated production of IL-6 was associated with fatigue the following day (ΔR²=.17, p=.05). Mediation analyses showed that slow wave sleep, but not REM sleep duration, mediated the relationship between evening levels of IL-6 production and daytime fatigue. These results indicate that increases in stimulated monocyte production of IL-6 may be associated with decreases in slow wave sleep and increases in REM sleep duration. Relative loss of slow wave sleep may be one pathway through which cellular inflammation leads to daytime fatigue.

Links between behavioral factors and inflammation.

This review focuses on the biobehavioral factors that show robust associations with markers of inflammation and discusses the following variables: diet, smoking, coffee, alcohol, exercise, and sleep disruption. Each of these variables has been assessed in large-scale epidemiological studies, and many of them have been assessed in clinical and experimental studies as well. Treatment strategies that target biobehavioral factors have the potential to complement and enhance the benefit of anti-inflammatory medicines.

Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine.

BACKGROUND: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Propranolol affects stress-induced leukocytosis and cellular adhesion molecule expression.

In this study, the impact of the beta-adrenergic antagonist propranolol on resting and acute psychological- and physical-stress-induced circulating leukocyte numbers and the density of cellular adhesion molecules was investigated. In a randomized double-blind crossover design, 45 healthy volunteers performed a 15-min public speaking task and 21 subjects performed a 16-min bicycle exercise after 5 days of ingesting a placebo and after 5 days of ingesting 100 mg/day propranolol. One week of ingesting propranolol modestly elevated the numbers of CD62L+ (P<0.019) but not CD62L- T-lymphocytes. Moreover, propranolol preferentially blunted-psychological stress-induced increases in naïve T-helper (CD4+CD62L+; P<0.049) and naïve T-cytotoxic lymphocytes (CD8+CD62L+; P<0.003), as well as activated T-cytotoxic lymphocytes (CD8+CD29+; P<0.005). However, exercise-induced increases in leukocyte numbers were enhanced following propranolol treatment (P<0.04). In contrast to the effect on the numbers of adhesion-molecule-bearing cells, there was only a modest effect of propranolol on stress-induced alterations of the density of CD62L, CD54 and CD11a. In this study, propranolol treatment interfered with the adrenergic regulation of circulating leukocyte numbers by blunting psychological stress effects but enhancing exercise effects. Propranolol affected the cell activation status to a lesser extent, as reflected by the density of adhesion molecules.

Interleukin-6 and tumor necrosis factor-alpha production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways.

OBJECTIVE: The aim of the study was to assess the effects of three different methods of acute activation of the sympathetic nervous system on lipopolysaccharide-induced in vitro production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). METHODS: Thirty-two healthy volunteers performed speech and exercise tasks and underwent a 30-minute infusion of isoproterenol. RESULTS: As expected, acute activation of the sympathetic nervous system led to leukocytosis, including increases in lymphocyte, monocyte, and granulocyte populations (p values <.05). Lipopolysaccharide-induced IL-6 production was increased after both the speaking and exercise tasks (p values <.001), whereas TNF-alpha production was elevated only after exercise (p<.05). In contrast, infusion of isoproterenol inhibited TNF-alpha production (p<.001) and caused no change in IL-6 production. CONCLUSIONS: In response to the challenges, IL-6 and TNF-alpha production showed different profiles. Purely beta-agonist stimulation led to downregulation of TNF-alpha production, providing evidence of the antiinflammatory effect of in vivo beta-receptor activation. The enhanced production of both cytokines after exercise, and of IL-6 after the speech task, can be best explained by a simultaneous upregulation of proinflammatory and inflammation-responding mediators. These effects may have an important role in controlling the immune response to acute psychological and physical stress.

Leukocyte adhesion molecule expression and T cell naïve/memory status following isoproterenol infusion.

This study examined adhesion molecules on peripheral leukocytes following a 30-min infusion of the beta-adrenergic agonist isoproterenol in 23 healthy subjects. In response to isoproterenol, the number of CD8 +CD62L- T cells and both CD62L+ and CD62L-natural killer (NK) (CD3 CD16+ 56+) cells increased markedly in circulation (p < 0.001). In addition, the surface density of CD62L was significantly lower on both CD8+ and CD4+ T cells (p < 0.001). Plasma levels of soluble CD62L remained unchanged, arguing against an isoproterenol-induced shedding of L-selectin. In contrast to CD62L, the surface density of the beta2 integrin LFA-1 (CD11a) was higher on circulating lymphocytes (p < 0.001) (but not monocytes or lymphocytes) post-infusion. Isoproterenol also led to a mobilization of memory/activated CD8+CD29high T cells (p < 0.01), but had no significant effect on the number of circulating CD8+ CD45RA+ CD62L+ naïve T cells. beta blockade with the non-specific antagonist propranolol eliminated these isoproterenol-induced effects.

Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans.

OBJECTIVE: Life stress is hypothesized to alter the dynamic regulation of the autonomic, neuroendocrine, and immune systems. This study examined the effects of antecedent chronic life stress on psychological and physiological responsivity after acute challenge with a psychological stressor. METHOD: Using a within-subject mixed design, male volunteers with (N = 12) and without chronic life stress (N = 11) were administered a 12-minute laboratory stressor (mental arithmetic) vs a video control. RESULTS: Acute psychological stress induced subjective distress, increases of circulating concentrations of epinephrine, norepinephrine, beta-endorphin, adrenocorticotropic hormone (ACTH), and cortisol, and a selective redistribution of natural killer (NK) cells into the peripheral blood as compared with the video control condition. Although the two groups were almost identical at baseline in psychological, sympathetic, neuroendocrine, and immune domains, the chronic stress group showed greater subjective distress, higher peak levels of epinephrine, lower peak levels of beta-endorphin and of NK cell lysis, and a more pronounced redistribution of NK cells in response to the acute psychological challenge than the controls. Furthermore, the acute stressor induced a protracted decline in NK lysis per NK cell in the chronic stress group but had no effect in the controls. CONCLUSIONS: In summary, when persons who are undergoing chronic life stress are confronted with an acute psychological challenge, an exaggerated psychologic and peak sympathomedullary reactivity occurs that is associated with decrements in individual NK cell function and is protracted beyond termination of the stressor and sympathomedullary recovery.

Longitudinal analysis of multiple indicators of health decline among spousal caregivers.

The hazards for experiencing major health events were studied longitudinally among 150 spousal caregivers of Alzheimer's disease (AD) patients and 46 married control participants. Based on longitudinal assessments from one to six years, the hazards of reaching any of three health events (extended physical illness or disability > 1 month, unhealthy medical rating from a nurse interview, or hospitalization) were not significantly different in a group comparison of caregivers to controls (Cox proportional hazards assumption, p > .05). However, there was a trend [X2(1, N = 107) = 3.13, p = .08] for caregivers to have a greater hazard for serious illness. Among caregivers only, a greater hazard for reaching at least one of these health events was associated with providing more activities of daily living (ADL) assistance [X2(1, N = 125) = 3.83, p = .05] but not with problem behaviors of the AD patient (p > .05). These results suggest that providing extensive ADL assistance may have health implications for spousal AD caregivers, while caregiving, per se, does not. Furthermore, these physical health impacts of caregiving may be best characterized using multidimensional assessments. Contrary to our guiding hypothesis, caregivers encountering more problem behaviors of their AD spouse were less likely to be hospitalized, X2(1, N = 145) = 5.88, p = .02. This finding may reflect a reluctance by caregivers to schedule necessary medical care when their spouses are most problematic, and this may have further long-term health implications for caregivers.

Modulation of immune cell function by the autonomic nervous system.

This review discusses some of the major findings implicating the autonomic nervous system in the regulation of immune function. The sympathetic nervous system, the primary focus of this line of research, directly innervates the major lymphoid organs, and physiological release of sympathetic neurohormones at these sites has been documented. Leukocytes have been shown to express receptors for catecholamines, as well as neuropeptide Y, and studies in vitro and in vivo have indicated that occupation of these receptors by the appropriate ligands produces functional changes in immunological cells. Finally, altered sympathetic regulation may underlie some of the immunological abnormalities observed in chronic stress, clinical depression, and ageing.

Natural and cellular immune responses in Flinders sensitive and resistant line rats.

Major depression is associated with impairments in natural and cellular immune responses. This study characterized baseline natural and cellular immune function in the Flinders Sensitive Line (FSL) genetic animal model of depression and in Flinders Resistant Line (FRL) controls. Splenic natural cytotoxicity per natural killer (NK) cell was significantly lower in the FSL rats, suggesting that NK cells are less activated at rest in the FSL rats than in the FRL controls. Neither lymphocyte proliferative responses nor interleukin-2 production differed between the two strains. Resting baseline concentrations of plasma adrenocorticotropic hormone and corticosterone were similar between the FSL and FRL rats, indicating that hypothalamo-pituitary adrenal axis activation did not mediate immunological differences. FSL rats show abnormalities in natural immunity similar to those found in clinically depressed human beings, indicating that this animal model may be useful in understanding the neural and neuroendocrine mechanisms associated with immune alterations in depression.

Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor.

NBXFO hybridoma cells produced both the membrane and secreted isoforms of macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+ macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor cells. In cytotoxicity studies, M-CSF activated macrophages and freshly isolated macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the possibility that contaminating lipopolysaccharide (LPS) was responsible for the delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the secreted isoform of M-CSF, transferred the ability of macrophages to kill these transfected T9 cells in a mM-CSF dose-dependent manner. Macrophage-mediated killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide inhibitor, N-omega-nitro-arginine methyl ester (NAME), did not effect macrophage cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when cultured in the presence of an equal number of the mM-CSF transfectant cells were not killed, indicating specific target cell cytotoxicity by the macrophages. Electron microscopy showed that macrophages were capable of phagocytosizing mM-CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible mechanism of this cytotoxicity. This study indicates that mM-CSF provides the necessary binding and triggering molecules through which macrophages can initiate direct tumor cell cytotoxicity.

A role for CRH and the sympathetic nervous system in stress-induced immunosuppression.

Central CRH coordination of the behavioral and physiologic sequelae of stress has been well established, and so it is parsimonious to suggest that CRH might also coordinate the immunologic sequelae. The studies presented here lend support to this suggestion. CRH administration into the brain was shown to modulate aspects of both cellular and humoral immune function, and the inhibition of CRH release in the brain following stress inhibited stress-associated immunosuppression. The effects of CRH appear to be mediated by the sympathetic branch of the autonomic nervous system, as chemical sympathectomy and pharmacological blockade of beta-adrenergic receptors both reversed the effects of CRH on immune function. In contrast, removal of the adrenal glands did not alter the immunologic effects of CRH. These links among CRH in the brain, sympathetic activation, and immune function suggest the possibility that immune function may be altered in other conditions characterized by elevated sympathetic tone, such as depression and aging, and that these alterations may be attributed to CRH dysregulation in the brain. These studies shed light on the intricate relationship between the brain and the immune system, and also illuminate its complexity. The differential regulation of CRH in the brain and the periphery is one example of the latter. These findings also set the stage for potential clinical intervention with CRH antagonists, for example, to treat compromised immune function associated with chronic stress, depression, or aging.

Neuropeptide Y inhibits in vivo specific antibody production in rats.

The sympathetic neurotransmitter neuropeptide-Y (NPY) is hypothesized to play a role in the in vivo modulation of immune responses. This study examined the effects of intraperitoneal administration of NPY on specific antibody responses to keyhole limpet hemocyanin (KLH) in rats. Antibody levels were repeatedly measured by enzyme-linked immunosorbent assay before and after intraperitoneal immunization with KLH. NPY induced a dose-dependent inhibition of IgM and IgG antibody responses following immunization with either physiologic or supraphysiologic doses of antigen. These in vivo results suggests that NPY may be involved in endogenous modulation of immune responses.