The patterns of malaria caused by Plasmodium falciparum are influenced by environmental factors, including endemicity and intensity of transmission. For example, children residing in hypoendemic areas commonly suffer from severe illness characterized by cerebral malaria, whereas children residing in holoendemic areas are more likely to experience parasitemia associated with severe anemia. It is quite possible that immune processes might have a profound impact upon the clinical manifestation of disease independent of the parasite density in the bloodstream. Since the placenta is a repository for blood-stage plasmodial antigens, we hypothesize that infants born to mothers who experience malaria during pregnancy develop tolerance or suppressive mechanism to blood stage antigens in utero. During subsequent malaria infections, the age-related acquisition of protective immunity is defined by the T cell repertoire that has been shaped by an early exposure to malaria antigens. We propose that the affected neonatal immune responses are reflected by the expression of characteristic phenotypic markers and immunologic functions of T cells and monocytes recoverable from cord blood cells. The following specific aims are proposed to examine these issues using cord blood specimens obtained at the time of delivery from primigravida women in The Gambia, in a region where high endemicity prevails with seasonal fluctuations in transmission intensity: (1) To determine if T cell reactivities of cord blood mononuclear cells differ between pregnancies complicated by malaria compared to pregnancies during which malaria did not occur. The analysis will include proliferative T cell responses to blood-stage antigens in the form of schizont-infected red blood cells, or protein and peptide antigens; lymphokine profiles of the blood-stage antigens-responding T cells; T cell subsets distinguished by cell surface markers in response to exposure to blood-stage antigens. (2) To evaluate if malaria infection during pregnancy affects the maturation of cord blood monocytes. This analysis will include: investigation of lymphokine profiles of ex vivo monocytes; obtained from cord blood from pregnancies with and without malaria; lymphokine production upon further in vitro stimulation with blood-stage antigens; induction of cell surface markers under the same conditions. Understanding of these early responses is essential for future studies seeking to elucidate mechanisms underlying age-related protective immunity, a pivotal point in the development of malaria vaccines.
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