Infant monkeys with different cellular immune and proinflammatory cytokine responses will be created by experimentally manipulating pregnancy conditions and used to determine the significance of individual variation in immune competence for infectious disease. This nonhuman primate model will further investigate how two types of prenatal conditions affect infant development, alter cellular immunity, and result in differential risk for and response to viral infection. The present manipulations involve maternal stress and endocrine activation shown previously to affect postnatal immunity. The infectious challenge will be influenza virus, focusing on viral shedding, antibody responses, cytotoxic T lymphocytes, cytokine levels, and symptom expression. Study 1 will compare control and disturbed infants generated from pregnancies involving acute daily stress for 6 weeks of the 24-week pregnancy. The disturbance is induced either early or late in gestation, because the timing has different postnatal immune consequences. The manipulations in Study 2 involve maternal endocrine activation, induced by daily injections of ACTH over a 2-weekperiod. Maternal hormone treatments will occur during the same early and late gestational periods as the psychological stressor to determine if comparable effects on fetal development occur.
The aim of Studies 3 and 4 shifts to the capacity to elicit protective immune responses via vaccination in the immuno-different monkey infants. During the first 6 months after birth, the immune panel focuses on proliferative responses, cytolytic activity, and cytokine release, and the sensitivity of lymphocytes to hormone feedback. The set point at which corticosteroids regulate and inhibit immune responses may be established during fetal life. The predictive value of this immune assessment will then be ascertained through infection of the monkeys with influenza virus when they are eight months old. Antibody and cytotoxic T lymphocyte (CTL) responses, and cytokine release and viral shedding in nasal secretions will be determined. Subsequently, in Studies 3 and 4, the ability to elicit protective immunity through vaccination prior to infection will be evaluated. This program would be the first to elucidate the prenatal basis of individual variation in immunity with respect to viral infection, using infant primates derived from carefully controlled pregnancies and well-characterized developmental trajectories.
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