Prenatal sensitization to W. bancrofti is hypothesized to be an important variable that affects the host's immune response and subsequent risk of infection and clinical disease. Antigens or anti-id antibodies that cross the placenta have been suggested to induce antigen (Ag)-specific tolerance and prevent disease. Instead we have observed that the fetus becomes sensitized to filarial antigens in utero based on the identification of filarial Ag- specific T and B cells in cord blood. This immunity persists for at least 2 years after birth in the absence of natural infection. This proposal tests the hypothesis that filarial Ag-specific immunity acquired in utero significantly influences susceptibility to infection, as well as the severity of sub-clinical lymphatic pathology in children. Fetal responses to filariasis can also alter the host immune response to other antigens. We have shown that BCG vaccination of newborns sensitized to filariasis in utero skews this immunity away from a protective type I IFN-g response. This project will examine the impact of in utero sensitization on the long-term immune response to BCG and Hemophilus influenza type B polysaccaride conjugate vaccines (Hib) administered during infancy. This study will examine the broader question of how fetal exposure to exogenous antigens may affect the ontogeny of the fetal immune response. We hypothesize that fetal exposure to exogenous Ags primes the fetal immune system and enhances children's antibody affinity maturation and capacity to synthesize anti-polysaccharide antibody and polyclonal IgG and IgA after Hib vaccination. This project builds on an established cohort of over 300 infants for which filarial-specific fetal immunity has been determined. These and newly recruited infants will be followed prospectively to determine the period to first infection, along with lymphatic pathology and immunity associated with early exposure and/or infection.
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