Description): This proposal is to study mechanisms of immunity to viral vaccines in infancy. By using measles immunization to investigate developmental changes in an infant's response, the investigator and his coworkers have determined that infants have reduced T- cell proliferation, dimished production of antigen-specific interleukin-12 (IL-12), and lower levels of interferon-gamma (IFN-gamma) enhancement to exogenous IL-12. Observed B-cell defects included decreased neutralizing antibody titers to measles in the youngest infants, despite the absence of interference from passive antibodies. This proposal is to study mechanisms of immunity that may explain the observed defects, and to distinguish if these deficiencies are unique to measles to represent an inherent limitation in the host responses to viral vaccines in infancy. The first goal will be to study the T-cell expression of CD40 ligand (CD40-L) in infants since this T-cell derived cytokine is necessary for providing B-cell help for antibody production and isotype switching. CD40-L is also crucial for primary T-cells, particularly for production of IFN-gamma, as well as being a key activator of mononuclear phagocytes of production of IL-12. The investigator will look at both mitogen-induced CD40-L expression at 6, 9, and 12-months of age and antigen-specific expression at the level of mRNA. Limitations in T-cell production of IFN-gamma will also be evaluated by measuring mRNA levels. In an attempt to investigate the capacity of infant B-cells, the investigators will perform in vitro stimulation of peripheral blood mononuclear cells (PBMC) and measure IgG measles antibody, after providing T-cell help with anti CD40 and cytokines. The next goal will be to study whether there are age-related, developmental changes in the induction of mumps specific CD4+T-cell proliferation, including Th1 and Th2-like cytokine production, and neutralizing antibody titers. The effect of passive antibodies on these responses will be evaluated. The fourth objective is to examine the ontogeny of the infant host response to major measles viral proteins. Purified proteins will be used in assays for T-cell proliferation and cytokine production, to determine if specific proteins drive Th1 versus Th2-like CD4+ T-cell responses.
