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The gestational experience of a mother can influence the intrauterine environment she provides her own offspring, allowing prenatal events to affect pregnancy outcomes across several generations. Using a multigenerational database, we determined the reproductive consequences for rhesus monkeys descended from small-for-date and large-for-date birth weight matrilines. Both the maternal half-brothers and -sisters of large-for-date infants exhibited enhanced fetal growth, but for small-for-date probands, only the maternal half-sisters experienced significant intrauterine growth constraint. In addition, the growth-restricted females were at higher risk of poor reproductive outcomes in adulthood, and they perpetuated the matrilineal birth weight pattern by selectively constraining the fetal development of their daughters. Collectively, these findings suggest a mechanism for the intergenerational persistence of suboptimal pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Background: A retrospective analysis was conducted on necropsy records from a large rhesus monkey colony to evaluate the age-related prevalence of endometriosis.Methods: A total of 314 records collected over a 15-year period were analyzed, yielding 66 monkeys with histologically verified endometriosis and 248 control subjects.Results: The analyses demonstrated that the incidence of endometriosis increases progressively across the life span, ultimately impacting 21-45% of aged monkeys over 20 years of age.Conclusions: Because mild disease is often not diagnosed premortem, the endocrine and immune sequelae of endometriosis may be a potential confound in even nonreproductive research with aging primates. Prior research-related events influence the occurrence and severity of endometriosis in these long-lived animals, and specifically could have contributed to the high prevalence of endometriosis in this particular monkey colony. [ABSTRACT FROM AUTHOR]

Fourteen female monkeys (Macaca mulatta) received a trivalent influenza vaccine and antibody response was determined by a change in plasma antibody content (ELISA) before and after vaccine. Lymphocyte cultures were also established from these monkeys and the level of antibody response did not correlate with mitogen-induced lymphocyte blastogenesis or natural killer cell function. In vitro anti-influenza antibody synthesis, however, was found to correlate well with the in vitro response. That is, monkeys who were non-responders, as determined by lack of change in plasma antibody content, were also non-responders in vitro. Accordingly. we believe that vaccine response is not necessarily a measure of immune competence but its measurement may, none the less, have clinical utility. The excellent correlation of in vivo and in vitro response provides predictive value for the in vitro test. Furthermore, because the correlation is good, the in vitro test may be useful as a tool in immunopharmacology and toxicology. [ABSTRACT FROM AUTHOR]

The autopsy records between 1980 and 1995 of 399 female rhesus monkeys (Macaca mulatta) at the Wisconsin Regional Primate Research Center were examined. Spontaneous endometriosis was found in 81 (20%) of the animals. The mean (+/- SD) ages at death for animals with and without endometriosis were 20.7 +/- 5.5 (range 10-35) and 13.4 +/- 7.7 (range 4-37) years respectively. Many of the animals had been exposed to experimental procedures, including laparoscopies, hysterotomies and oestradiol implants, and these were examined as possible risk factors for endometriosis. Of the 81 affected animals, 62 were matched to unaffected controls for age at death (to within 1 year) and year of death (to within 2 years) and the effect of various factors on the development of endometriosis was determined using conditional logistic regression. Exposure to three or more oestradiol implants or one or more hysterotomies were both significant risk factors, with estimated relative risks of 9.7 (95% confidence interval 2.5-37.2) and 5.8 (95% confidence interval 1.6-20.2) respectively. Animals that had been exposed to one or more laparoscopies showed no increased risk for developing endometriosis. These findings provide insight into the aetiology of the disease in women. ?2P51 4RR00167 [ABSTRACT FROM AUTHOR]

Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging., (Published by Elsevier Inc.)

This study examined the effects of social support on dysmenorrhea and whether social support moderates the relationship between negative emotions and painful symptoms. Women (N = 184) completed questionnaires on menstrual symptoms, depression, anxiety, and social networks. Depression and anxiety were strongly associated with menstrual pain. Women who no longer had access to their prior support providers manifested more symptoms than did women with stable social relations. In addition, this disruption in their social networks moderated the relationship between distress and menstrual pain. Results indicate that loss of social support is a significant contributor to menstrual symptoms and point to the importance of considering specific aspects of social support in studying its effect on health.

Several factors associated with the age-related decline in immunity were examined in three studies on aged rhesus monkeys. Natural killer (NK) cell activity was found to be low in many monkeys after 20 years of age, but exceptionally long-lived animals, older than 25 years, often had vigorous cytolytic responses. When NK activity was decreased in an aged monkey, it was predictive of fewer years of survival and a younger age at death. This prediction of mortality was associated with one nonimmune biomarker of aging in the monkey: nail growth rate. Monkeys with very slow nail growth and low NK activity were likely to die sooner. Although these findings might suggest an immutable course for the aging process, the housing conditions of old monkeys also had a pronounced effect on their NK activity. The highest NK responses were found in old monkeys housed with just one other old animal when compared to living alone or with just a young, juvenile monkey. It remains to be determined whether this type of psychosocial influence could have a sustained effect on immunity and ultimately change the pace of aging and time to mortality.

Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Studies also suggest that immune mechanisms participate in TCDD-mediated toxicity and the pathogenesis of endometriosis. Thirteen years after TCDD treatment was terminated, we characterized the phenotypic distribution of peripheral blood mononuclear cells (PBMC) from TCDD-exposed and -unexposed rhesus monkeys and determined the ability of these cells to produce cytokines and exert cytolytic activity against NK and T-cell-sensitive cell lines. We also determined whether elevated serum levels of TCDD, dioxin-like PHAH congeners, and triglycerides correlated with changes in PBMC phenotype or function. For all animals, TCDD exposure correlated with increased PBMC tumor necrosis factor-alpha (TNF-alpha) secretion in response to stimulation by T-cell mitogen and decreased cytolytic activity against NK-sensitive target cells. Furthermore, increased production of this cytokine by PHA-stimulated leukocytes was associated with elevated serum triglyceride levels. Leukocyte TNF-alpha secretion in response to viral antigen and PBMC production of interferon gamma (IFNgamma), IL-6, and IL-10 following exposure to mitogen or antigen were unaffected by previous TCDD treatment. Although TCDD exposure was not associated with changes in PBMC surface antigen expression, elevated serum concentrations of TCDD, 1,2,3,6,7,8-hexachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNF-alpha by mitogen-stimulated PBMC. These findings indicate that TCDD-exposed rhesus monkeys with endometriosis exhibit long-term alterations in systemic immunity associated with elevated serum levels of specific PHAH congeners.

The capacity of prenatal stress to disrupt the placental transfer of maternal antibody was evaluated in neonatal squirrel monkeys (Saimiri boliviensis peruviensis) gestated under different pregnancy conditions. Normal squirrel monkey offspring (n = 63) were compared with infants generated from pregnancies that involved either a single or 3 periods of disturbance (ns = 21 and 29, respectively). At parturition, levels of antibody (IgG) were determined in mothers and neonates. Only the chronic disturbance condition significantly altered antibody levels in the mothers, resulting in lower IgG. Antibody transfer to the fetus was also affected only by chronic disturbance. In this case the effect was bidirectional, influenced by the sex of the infant. Males were born with lower levels, whereas female infants actually had higher-than-normal IgG, despite lower titers in their mothers. Because virtually all IgG is derived from the prenatal transfer of maternal antibody, it indicates that the sex of the fetus differentially affected this placental process. The IgG receptor may have been up-regulated selectively on the placentas of female fetuses, compensating for reduced antibody in the disturbed mothers.

This article reviews current animal and human data regarding possible adverse fetal effects from antenatal steroid treatment. Although it is now well accepted that such treatment is of benefit to fetal lung development, the potential for adverse fetal outcomes as a result of single or multiple glucocorticoid dosing has not been widely recognized. There are now growing concerns, based on animal and some human data, that repeated antenatal doses could lead to a decrease in birth weight, a decrease in fetal brain and other organ size, and abnormal neuronal development. Previous investigations have been hampered by nonstandardization in the type of glucocorticoid, route of delivery, timing of administration, and number of treatment courses. It is recommended that these concerns be addressed through large randomized, controlled clinical trials. In the meantime, it would be prudent to minimize antenatal steroid treatments to a single course with repeated dosing only if there is a persistent threat of preterm delivery. The practice of giving weekly injections of steroids starting at fetal viability and continuing into the third trimester is not supported.

Many factors during fetal life and early infancy have been found to affect the development of immune responses in animals. This study investigated whether acute exposure of the fetal monkey to high levels of corticosteroids would also have a lingering effect on the expression of immune responses still manifest postpartum in yearling juveniles. One month prior to parturition, pregnant rhesus monkeys were administered dexamethasone for two days. Lymphocyte proliferative responses to mitogen were then examined in their offspring when they were between 1.0-1.5 years of age. In addition, cell sensitivity to corticosteroid feedback was assessed by testing the ability of a gradation of cortisol doses to inhibit proliferation. Monkeys generated from dexamethasone-treated pregnancies tended to have lower responses to concanavalin A. Further, their cells were less sensitive to in vitro incubation with cortisol, suggesting that elevated adrenal activity in vivo had downregulated hormone receptors on their cells. These findings concur with the view that steroidal hormones in utero can influence the fetal immune system, resulting in prolonged effects on immune responses after birth. The similarity of the dexamethasone condition to the clinical treatment used in obstetrical practice raises a potential concern about the widespread antenatal exposure of premature infants to steroidal drugs.

Brain endothelial cells (BECs), specialized cells of the blood-brain barrier (BBB), are ideally positioned to monitor and respond to events in the periphery. The present study examined their potential role in transducing immune signals to the brain and in responding to noxious stimuli. BECs were isolated from rhesus monkeys at 3 age points (fetal/neonatal, adult, and very old animals). Cells were then challenged in vitro with either an immune stimulus (interleukin-1 beta (IL-1 beta), or lipopolysaccharide (LPS)) or an oxidative challenge (hypoxia). BECs released interleukin-6 (IL-6), which is known to have neurotrophic and neuroprotective functions. Furthermore, higher amounts of IL-6 were released in both baseline and stimulated conditions by BECs derived from aged animals. This research indicates a pathway whereby immune signals may be communicated to the CNS and has revealed one way that the BBB may protect neuronal survival under challenge conditions.

The capacity of the neonate to respond to nonself antigens was evaluated in infant monkeys born after normal and disturbed pregnancies. Mixed lymphocyte cultures were used to test the infants' proliferative responses to mitomycin-treated stimulator cells, either from a genetically unrelated animal or from a virally transformed monkey cell line. Periods of daily stress for 6 weeks in mid-late pregnancy (months 3.0-4.5) resulted in a significant decrease in proliferative responses, whereas the same stressor early in pregnancy (months 1.5-3.0) increased responses by the neonate's cells. Similar to the late stress effect, an inhibition of proliferative responses by neonatal cells was induced by dexamethasone administered for 2 days late in pregnancy at 4.5 months after conception, 1 month before term. These findings demonstrate that certain immune responses at birth are extremely sensitive to prior prenatal events. Further, the bidirectional changes indicate that there may be critical periods in gestation when the same extrinsic events have radically different effects on the fetus.

The integrity of the indigenous microflora of the intestines after maternal separation was investigated in infant rhesus monkeys to determine whether psychological stress may lead to an internal environment conducive to pathogen infection. The stability of the indigenous microflora were estimated by enumeration of total and gram-negative aerobic and facultatively anaerobic bacterial species, specifically Lactobacilli, from coprocultures taken before and after maternal separation. In addition, behavioral and cortisol responses to separation were correlated to the microflora. A significant decrease in fecal bacteria, especially Lactobacilli, was evident on day 3 postseparation, with a return to baseline by the end of the week. The drop in the microflora was correlated with the display of stress-indicative behaviors, but not with cortisol secretion. In addition, infants who displayed numerous stress-indicative behaviors were more susceptible to opportunistic bacterial infection. These results suggest that strong emotional reactions to disruption of the mother-infant bond may increase vulnerability to disease., (Copyright 1999 John Wiley & Sons, Inc.)

Two studies were conducted to determine whether attenuated strains of Salmonella typhimurium, currently being investigated as possible vectors for mucosal vaccines, are able to respond to norepinephrine (NE). Bacteria were tested for NE responsiveness before and for 1 week after passage through juvenile rhesus monkeys. NE significantly increased the growth of the attenuated bacteria after being shed from the animal, but not before animal infection. Follow-up in vitro tests were performed by passaging the bacteria in Lauria-Bertani (LB) broth with or without selective antibiotic for the attenuation insert and supplementing with NE. NE increased the growth of bacteria passaged in LB broth with no selective antibiotic, but not in bacteria passaged in LB broth with selective antibiotic. These results show that the attenuated bacteria assumed to be safe for use as a vaccine are able to respond to environmental stimuli, such as NE, and change their characteristics. The results suggest that there may be problems with the stability of attenuated bacteria used as vectors for mucosal vaccines.

The possibility that brain damage results in a sustained dysregulation of lymphocyte responsiveness to the lymphokine, interleukin-2 (IL-2), was investigated in individuals who had experienced a unilateral stroke in adulthood or who presented with spastic hemiparesis since childhood. Following verification of unilateral brain damage via neuromotor assessment, and determination of their health status, blood samples were obtained to evaluate a panel of immune measures. Soluble interleukin-2 receptor (sIL-2R) and lymphocyte proliferative and cytolytic responses in the subjects with stroke or cerebral palsy were compared to age- and gender-matched controls. In addition, lymphocyte populations were enumerated via flow cytometry, and lymphocyte cyclic AMP (cAMP) levels were determined. Circulating blood levels of sIL-2R were significantly elevated in all individuals that had experienced unilateral brain damage. Cytolytic activity also failed to be stimulated to the normal level by in vitro treatment of lymphocytes with IL-2. Further, lymphocytes from the stroke subjects proliferated significantly less after mitogen and IL-2 stimulation. These functional differences were not accounted for by an abnormal leukocyte profile, although phenotypic analyses revealed subtle differences in the natural killer cell subsets. Overall, the findings indicate that individuals with brain damage may not respond appropriately when immune activation is required. These immune differences appear to be a stable trait given that they were manifested after both perinatal and adult brain insult in otherwise healthy, independently living individuals.

The ability of both exogenous and endogenous glucocorticoids (GCs) to inhibit proinflammatory cytokine production was investigated in vivo. Specifically, we investigated the effects of elevated GC levels on interleukin (IL)-1-induced release of IL-6 into both blood and cerebrospinal fluid (CSF). Three experiments were conducted in rhesus macaques to elevate corticoid levels for at least 4 h before administration of IL-1beta. The first study used dexamethasone pretreatment, the second utilized ACTH to stimulate endogenous cortisol release, while the third relied on a psychological challenge to stimulate the hypothalamic-pituitary-adrenal axis. Contrary to our a priori predictions, none of these treatments attenuated the IL-1-induced release of IL-6 into CSF. Additionally, the pattern in the blood response was similar, such that the IL-6 response was not blocked, although there was a trend toward a reduction of this response. These data indicated that the IL-1-induced IL-6 response is for the most part resistant to corticosteroid influence, such that even when a partial inhibition was sometimes evident in blood, cytokine release in the central nervous system was not affected.

Although most clinicians believe that social support has beneficial effects on health, the mechanisms mediating this relationship have not been clearly established. We examined the direct effect of social support on several immune measures and its role in moderating the response to academic exams in healthy and asthmatic adolescents. Three types of students--healthy, mild asthma, and severe asthma--completed social support and stress questionnaires and gave blood samples during the midsemester and final exam periods. Social support and natural killer cell (NK) function showed a significant reduction during exams in both healthy and asthmatic adolescents. Social support, however, did not have a direct effect on immune responses. Nevertheless, high social support appeared to attenuate the magnitude of exam-induced reduction in NK activity, suggesting a role for social support in protecting against immune decrements during times of stress.

Objectives: The purpose of this study was to investigate whether maternal endocrine activation during pregnancy would affect the neurobehavioral state of primate offspring in a manner similar to that observed in human infants from pregnancies involving maternal substance abuse or maternal stress., Method: Twenty-two rhesus monkey (Macaca mulatta) infants were derived from females administered either adrenocorticotrophic hormone (ACTH), which increased the mother's endocrine activity, or saline solutions for 14 consecutive days during mid-pregnancy. On days 15 and 30 postpartum, infants underwent brief separations from their mothers and were videotaped for later evaluation of neurobehavioral state., Results: Infants from mothers administered ACTH spent significantly more time in a drowsy state than did controls (p < .04), and the increased drowsiness tended to be most pronounced during the postseparation period, when acute stress was highest. In contrast, controls remained in a more active alert state (p < .03), presumably searching for their mother, a species-typical adaptive response to maternal separation. Female infants spent more time in distressed state than did males on day 15, and the proportion of time in distressed state decreased in all infants after administration of .2 ml of 24% sucrose solution., Conclusion: The results demonstrate that neurobehavioral state alterations are found in infants from mothers with increased endocrine activity during pregnancy. Neurobehavioral state disorganization can have an adverse impact on the human infant's concurrent and subsequent occupational performance. These findings establish the usefulness of the nonhuman primate model for advancing knowledge on early contributions to the development of human infant occupational behavior.

Proinflammatory cytokines [interleukin (IL)-1 and -6 and tumor necrosis factor-alpha] function within a complex network, stimulating the release of one another, as well as other cytokine agonists and antagonists. These interactions have not been as widely studied in vivo. Therefore, the following studies measured cytokines in blood and cerebrospinal fluid (CSF) from juvenile rhesus monkeys after intravenous administration of cytokines. IL-1 alpha and IL-1 beta were equally effective in elevating blood levels of IL-6. In contrast, IL-1 beta was the only cytokine that significantly elevated IL-6 levels in the CSF. Interestingly, both IL-1 and IL-6 increased levels of IL-1 receptor antagonist in the blood and comparably stimulated the release of cortisol. A second study confirmed that the IL-1-induced IL-6 in CSF was brain derived and not a result of diffusion from blood. This research extends studies of the cytokine cascade to the central nervous system (CNS), highlighting the brain response to peripheral activation.

Two studies were conducted to assess the potential long-term effects of prenatal stress on the cytokine-related inflammatory response in juvenile rhesus monkeys. Subjects were derived from two different pregnancy conditions. Study 1 involved endocrine activation of the pregnant female by daily adrenocorticotropic hormone (ACTH) injection across a 2-week period (days 120-133 post-conception). Pregnant females in Study 2 experienced a psychological stressor, 10 minutes per day, for a 6-week period (days 106-147 post-conception). When the offspring from these pregnancies were 1.5-2 years of age, they were administered recombinant human interleukin-1beta (rhIL-1beta) to stimulate the release of endogenous cytokines, elicit fever, and activate the hypothalamic-pituitary-adrenal (HPA) axis. Cerebrospinal fluid (CSF) and blood levels of interleukin-6 (IL-6) were measured, as well as cortisol levels and body temperature. The prenatal ACTH treatment altered the postnatal response to IL-1beta in juvenile offspring. These monkeys showed a significantly blunted response to the IL-1beta, with smaller increments in blood and CSF levels of IL-6 and diminished temperature responses to the IL-1beta. In contrast, the prenatal psychological stressor was not as potent and did not have lasting effects on this physiological response in juvenile monkeys. IL-1beta also induced significant increases in cortisol secretion, but this adrenal response was comparable in all monkeys. These data suggest that differences in the prenatal environment could have a selective effect on cytokine physiology accounting for individual differences in the inflammatory response.

T cell cytokines play an important role in mediating airway inflammation in asthma. The predominance of a Th2 cytokine profile, particularly interleukin (IL)-4 and IL-5, is associated with the pathogenesis and course of asthma. The aim of this study was to test the hypothesis that a stressful life event alters the pattern of cytokine release in asthmatic individuals. Thirteen healthy controls and 21 asthmatic adolescents gave blood samples three times over a semester: midsemester, during the week of final examinations, and 2-3 weeks after examinations. Interferon-gamma (IFN-gamma), IL-2, IL-4, and IL-5 were measured from supernatants of cells stimulated with PHA/PMA for 24 h. Cells from asthmatic subjects released significantly more IL-5 during the examination and postexamination periods, whereas cells from healthy controls released significantly more IL-2 during the midsemester and examination periods, thereby indicating a bias for a Th2-like pattern in asthmatics and a Th1-like pattern in healthy controls. IL-4 and IL-5 production showed a marked decrease during and after examinations in healthy controls, whereas this decline was absent in asthmatics. The ratios of IFN-gamma:IL-4 and IFN-gamma:IL-5 also revealed significant changes in the profile of cytokine release across the semester. These results indicate differential cytokine responses in asthmatics that may become pronounced during periods of cellular activation.

Cerebrospinal fluid (CSF) samples were collected from monkeys infected with SIVmac251 (SIV) or HIV-1/SIVmac chimeric viruses (SHIV(HXBc2) and SHIV(89.6P)) to investigate quinolinic acid (QUIN) levels in the intrathecal compartment. CSF levels of QUIN were elevated in the SIV-infected monkeys, especially in animals with end-stage disease, and in those infected with pathogenic SHIV(89.6P), but not after infection with the nonpathogenic construct SHIV(HXBc2). QUIN elevations occurred in association with reduced CD4+ and increased CD8+ lymphocytes, cellular alterations that were more pronounced in CSF than in the blood. These findings support the view that the intrathecal compartment provides a unique window on viral infection, and are in keeping with the a priori prediction that QUIN increases primarily in response to more pathogenic viral strains.

Immune responses to an academic stressor were examined in healthy and asthmatic adolescents with regard to their illness symptom reports. Eighty-seven high school students completed a health diary for 2 weeks and provided three blood samples during midsemester, final-exam, and postexam periods. During exam week, all students showed significant immunological alterations from baseline. Natural killer cell activity was significantly lower, whereas lymphocyte proliferation and neutrophil superoxide release were significantly higher. These immune changes tended to return toward baseline during the postexam period, but the enhanced neutrophil reactivity continued to rise. Overall, immunological responses were similar between asthmatic subjects and controls. Appropriate medical management may have accounted for this similarity. However, subtle group differences in the postexam recovery pattern and a continuous activation of inflammatory cell function following a stressor may warrant further investigation.

Lymphocyte cytolytic responses were assessed in 75 infant squirrel monkeys to investigate the influence of psychosocial disturbance on immunity. Four studies evaluated alterations in lytic activity during social separations from the mother lasting for 1-7 days. Lytic responses against target cells were markedly decreased during the first day of separation, and then gradually returned toward baseline levels. Although associated with a general lymphocytopenia in vivo, lower lysis was not mediated specifically by inclusion of fewer Leu11b+ cells in the in vitro assay. Multiple physiological processes probably converge to mediate the decrease in lysis. Treatment of the infant with RU486 to block corticosteroid hormone receptors or with naltrexone to antagonize opiate hormone action did not prevent the decrease in lytic responses from occurring. This research demonstrates that psychological disturbance can significantly impact immunity, but the recovery of normal functioning by 1 week also reveals the resiliency of the immune system, paralleling the time course of the infant's behavioral adaptation to this challenge.

Cellular immune responses were evaluated in 35 infant rhesus monkeys generated from two types of pregnancy conditions. Pregnant females were administered either saline or adrenocorticotropic hormone (ACTH) for 2 weeks between Days 120 and 133 postconception, approximately 1 month before parturition. After birth, lymphocytes obtained from infants in the ACTH condition failed to respond as readily to allogeneic cells in mixed lymphocyte cultures, proliferated less to Con A, exhibited lower suppressor function following stimulation with Con A, and showed lower cytolytic activity against target cells. For some measures, the prenatal effect was observed more consistently in male infants. Differences were evident with these in vitro immune assays through 6 months of age, indicating that acute disturbance during the prenatal period can have lingering effects on postnatal immunity.

To evaluate possible long-term effects of exposure to monoaminergic drugs, blood and cerebrospinal fluid (CSF) samples were collected from adolescent monkeys that had been treated with desipramine and fluoxetine in infancy. This evaluation focused on the number and type of leukocytes in CSF as a reflection of cell trafficking in the intrathecal compartment. Monkeys administered fluoxetine 2 years prior to the sample collection evinced significantly higher numbers of leukocytes in CSF than did either control or desipramine-treated subjects. The elevated cell count was accounted for primarily by increased numbers of CD4+ and CD8+ lymphocytes. The finding of higher cell numbers in CSF was replicated in a second sample from the fluoxetine-treated monkey obtained 1.5 years later. Because the cell profile in blood was unaffected by the prior drug treatments, these observations indicate a need for further study of serotonergic influences on regulation of the intrathecal compartment in the developing individual.

To evaluate cellular changes in the intrathecal compartment in response to psychological stress, cerebrospinal fluid (CSF) and peripheral blood (PB) samples were obtained from rhesus monkeys under baseline and challenge conditions. Juvenile monkeys separated from their social companions overnight had elevated cortisol, increased polymorphonuclear (PMN), and fewer CD4+ and CD8+ leukocytes in PB. In contrast, in CSF there were more CD4+ and fewer CD8+ leukocytes, raising the CD4/CD8 ratio. Dexamethasone given intramuscularly caused similar hematological changes; i.e. neutrophilia and lymphocytopenia with fewer CD4+ and CD8+ leukocytes in PB. However, it did not induce similar changes in CSF, indicating that the stress-related shift of CD4+ leukocytes in the intrathecal compartment involves physiological processes beyond adrenocortical steroids.

The behavioral effects of recombinant human interleukin-1 alpha (IL-1) in rhesus monkeys (Macaca mulatta) were assessed in 3 experimental paradigms: (1) a testing situation in which an initial quiescent period was followed by a challenge designed to evoke agitation; (2) a novel environment with a social partner; and (3) a working memory-dependent nonspatial cognitive task. In the first two experiments we replicated our previous observations that a high IL-1 dose (25 micrograms) induces somnolence in a quiet setting within 1 h. A lower IL-1 dose (1 ng) did not have these sedative properties, but both IL-1 doses significantly reduced the number of vocalizations made by the monkeys. In contrast, when the monkeys were challenged through direct eye contact with a human experimenter, the 25 micrograms IL-1 dose significantly increased agonistic behavior. Finally, performance on a working memory-dependent task (delayed non-matching-to-sample) was unaffected by doses of IL-1 ranging from 1 to 25 micrograms, possibly because the monkeys were tested after learning the task rather than during the acquisition phase. These results demonstrate that high levels of IL-1 in peripheral circulation can have potent behavioral effects in the nonhuman primate, but that the nature of the influence will depend on the context in which the animal is evaluated. Manifestation of cytokine-induced 'sickness behavior' appears to require a permissive environment.

The influence of academic examinations on immunity and lung function was investigated in 64 adolescents to determine if stress-related changes would differ between healthy and asthmatic students. Blood samples were collected on three occasions: 1 month prior, during, and 2-3 weeks after exams. Leukocyte subsets were enumerated, and in vitro assays were conducted to assess lymphocyte proliferative and cytolytic responses and neutrophil production of superoxides. Examinations elicited significant changes in several lymphocyte subsets and marked alterations in the three functional measures in all students. However, the magnitude and pattern of change did not differ between healthy and asthmatic students. Similarly, neither mild nor more severe asthmatics showed an exam-related decrement in lung function, as reflected by peak expiratory flow rate. This research validated that examinations are a salient cause of altered immune responses, but indicates that there is not a concomitant aggravation of inflammatory disease in well-managed asthmatics.

Two studies were conducted to investigate whether behavioral and physiological responses induced by administration of interleukin-1 beta (IL-1 beta) were also associated with changes in interleukin-6 (IL-6) and soluble IL-6 receptor levels (sIL-6R). Following intravenous injection of rhIL-1 beta, blood and cerebrospinal fluid (CSF) samples were collected from juvenile rhesus monkeys. Marked increases in IL-6 levels were evident at 1 h in both blood and intrathecal compartments. IL-1 beta also induced significant elevations in the release of ACTH and cortisol into the blood stream, and following high doses, the monkeys evinced signs of sickness behavior. The second study characterized the IL-beta dose-response relationship showing that these physiological changes were most evident at doses between 0.5 microgram and 1.0 microgram IL-1/kg body weight. Soluble IL-6 receptor concentration was also increased, but only in plasma. There was no detectable sIL-6R in CSF. The large release of IL-6 into CSF suggests that some behavioral symptoms may be due to intrinsic changes in central nervous system activity concomitant with the alterations in peripheral physiology.

Four experiments were conducted in aged rhesus monkeys to investigate how physical and psychological stressors influence the lymphocyte cytolytic responses against two target cell lines. An initial analysis of the lytic activity of various cell subsets against K562 and RAJI target cell lines suggested that both CD3+CD8+ and several CD3- subsets were responsible for lysis of the K562 cells. The RAJI cell line, in contrast, was killed primarily by CD3-subsets. To explore the implications of this differential mediation of lysis, cytolytic activity was evaluated after a physical challenge (surgery), a psychological disturbance (social separation), and in vitro incubation of lymphocytes with cortisol. The minor surgical procedure-laparoscopic examination-resulted in a significant decrease in lymphocyte cytolytic responses against both target cells 1 week postsurgery. In contrast, psychological disturbance elicited by changes in social relations caused a dual response, differentially affecting the lysis of either K562 or RAJI cells, dependent upon the type of behavioral reaction. Incubation of lymphocytes with cortisol in vitro indicated that lysis of both targets could be affected by corticosteroids, but the high concentration required (10(-6) M) suggested that the in vivo inhibition of cytotoxicity may not have been mediated by adrenocortical activation. Overall, the results highlight the value of utilizing multiple target cell systems in the analysis of cytolytic activity, especially in studies using nonhuman primates.

Thymosin-alpha 1 (thymosin alpha 1) and cortisol levels were evaluated in juvenile squirrel monkeys to investigate the influence of psychological disturbance on thymic and adrenal hormone activity. Hormone levels were assessed in peripheral circulation following removal of monkeys from their social group to establish the time course of thymosin and cortisol alterations. Thymosin alpha 1 was significantly decreased after social separation in association with increased adrenocortical activity, especially during the first day after being housed alone. The temporal pattern suggested that both hormone systems are involved in the acute inhibition of functional immunity observed following this type of psychological disturbance. A second study verified that the decrement in thymosin alpha 1 levels was replicable and also sensitive to psychosocial factors that influence the level of induced disturbance. In addition, changes in thymosin secretion could be attenuated partially by pharmacological inhibition of the cortisol response and opiate hormone action. Nevertheless, the decrease in thymosin alpha 1 secretion did not appear to be a secondary consequence of adrenocortical secretion, and instead probably emanates from a general shift in neuroendocrine activity.

Cellular components in free-flowing cerebrospinal fluid (CSF) of normal rhesus macaques were characterized. Microscopic counting enumerated the total number of leukocytes, percentage of polymorphonuclear cells (PMN), leukocytes with nonspecific esterase (NSE), and those reducing nitro blue tetrazolium (NBT). Flow cytometric analysis further identified CD4, CD8, CD14, and CD20 positive leukocytes. These experiments established reliable techniques for evaluating cellular components in CSF from rhesus macaques and documented the difference in the CD4/CD8 ratio between peripheral blood (PB) and CSF compartments under normal physiological conditions.

In animals, perturbations of the rearing environment have been shown to alter behavior, cognition, and physiology, including immune responses. In order to evaluate the effect of early rearing conditions on the development of immune responses in the infant primate, several immunological measures were assessed in rhesus monkey infants, nursery-reared (NR) or mother-reared (MR), from birth to 2 years of age. Rearing in the absence of the mother affected several aspects of cellular immunity. NR monkeys had significantly lower proportions of CD8 cells and lower natural killer cell activity than did MR monkeys. In contrast, their lymphocyte proliferation responses to mitogen stimulation were higher than those of MR monkeys. An attempt to behaviorally rehabilitate the NR infants at 1 year of age did not result in a recovery of normal immune responses. This study indicates that abnormal early rearing may have long-lasting effects on the immune system, which could have health consequences later in life.

Physiological and pharmacological doses of recombinant human interleukin-1 (IL-1) were administered intravenously to juvenile rhesus monkeys in order to evaluate its effects on immune and endocrine activity. Mitogen-induced lymphocyte proliferation was increased following 1-ng and 1-microgram doses of IL-1, but decreased following 10- and 50-micrograms doses. Natural killer cell cytotoxicity was also significantly reduced at the 10-micrograms dose and tended to be below baseline at the 50-micrograms dose. These changes were associated with marked neutrophilia observed after administration of IL-1. These results indicate that peripheral administration of IL-1 can either enhance or inhibit the numbers and responses of immune cells in rhesus monkeys depending on the dose administered. These responses may have been the result of differential activation of the endocrine system, because levels of pituitary hormones in plasma increased progressively with increasing doses of IL-1. Thus, the extent to which a particular dose of IL-1 induces the release of pituitary-adrenal hormones may be related to the direction and magnitude of the resulting changes in immune activity.

Maternal and fetal/infant antibody levels were assessed across pregnancy and at birth to evaluate the prenatal transmission of IgG in the rhesus monkey. Although some antibody was evident in the fetus by midpregnancy, the marked increase in IgG occurred primarily during the last two weeks of pregnancy. This delay until the end of pregnancy would result in low antibody titers in premature infants. In contrast, when gestation length was normal, the placental transfer of IgG was resistant to both dexamethasone treatment and a prolonged period of stress during pregnancy. This resiliency occurred despite an effect of prenatal stress on other aspects of infant development, including physical growth and the fetal synthesis of complement proteins.