The parasite growth rates were calculated as described in Materials and Methods, and the 95% confidence intervals were 2

The parasite growth rates were calculated as described in Materials and Methods, and the 95% confidence intervals were 2.3 to 18.5 merozoites/schizont for the animals immunized with PBS Tyrosine kinase inhibitor and given anti-MSP119 antibodies, 27.6 to 42.6 merozoites/schizont for animals immunized with PBS and given NMS, 5.5 to 14.4 merozoites/schizont for animals immunized with MSP119 and given anti-MSP119 serum, and 21.3 to 43.9 merozoites/schizont for animals immunized with MSP119 and given NMS. of antibody, and we concluded that an immune response focused solely on MSP119-specific antibodies is sufficient for protection. The data imply that the ability of natural contamination to boost an MSP119-specific antibody response should greatly improve vaccine efficacy. The 19-kDa carboxyl terminus of merozoite surface protein 1 (MSP119) is usually a leading malaria vaccine candidate (reviewed in reference 7). Previous studies have shown that protective immunity induced by MSP119 is dependent on a high titer of specific antibodies present at the time of challenge (1, 4,5) and an active immune response against the parasite of undefined specificity postinfection (6). Complete protective immunity induced by MSP119 requires the participation of both specific antibodies and CD4+ T cells. Previous studies exhibited that transfer of high-titer anti-MSP119 antibodies into immunodeficient (SCID, nude, BKO, CD4+ T-cell-depleted) mice delayed parasite growth, but the mice ultimately developed parasitemia and succumbed to contamination (6). In contrast, transfer of antibodies into normal mice can protect IKK-gamma antibody them. It thus appears that an active immune response postchallenge that is dependent on B cells and T cells is critical for MSP119-induced protective immunity (4). Since certain strains of normal mice that cannot themselves mount an antibody response to MSP119 (i.e., immunological nonresponders) can nevertheless be passively guarded by MSP119-specific antibodies, it appears that proteins other than MSP119 must be capable of protecting mice. However, the specificity of this active immune response postinfection has not been defined. In particular, it is not known whether an MSP119-specific response postinfection is sufficient for protective immunity. The possibility of a contribution from effector CD4+ T cells to MSP119-induced immunity has not been completely eliminated. Depletion of CD4+ T cells in MSP119-immunized mice can eliminate the protective immunity induced by MSP119 vaccination (1, 5). The mechanism by which CD4+ T cells contribute to the protective immunity remains unclear and needs further investigation. A number of CD4+ T-cell epitopes on MSP119, including a dominant epitope recognized by different strains of mice and referred to as p24, have been identified (13). Adoptive transfer of T-cell lines specific to p24 into nude mice does not safeguard the mice, suggesting that effector T cells may play only a minor role in protective immunity. However, T cells with other (undefined) specificities are known to be able to protect mice impartial of antibody (12), and it is possible that MSP119-specific CD4+ T cells contribute in an ancillary way to immunity and complement antibody-mediated protection. In this study, the nature and specificity of the immune response that develops following immunization with MSP119 and parasite challenge were investigated. By using an adoptive transfer system in which nude mice Tyrosine kinase inhibitor received p24-specific T cells and were then immunized with recombinant MSP119 to restrict the pre- and postchallenge immune responses to MSP119, the specificity of the active immune response following contamination was defined. We found that MSP119-specific antibodies alone can control parasitemia postchallenge and that effector T cells specific to MSP119 play no role in immunity. MATERIALS Tyrosine kinase inhibitor AND METHODS Experimental animals and parasites. Six- to eight-week-old normal and nu/nu (nude) female BALB/c mice were purchased from Animal Resources Center, Willeton, Australia. C57BL/6 -chain knockout (BKO) mice were obtained from the Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia, and were bred in our animal house facility. YM (a lethal strain) was used. Recombinant MSP119 protein and antigens. MSP119 of was Tyrosine kinase inhibitor produced in (yMSP119) as described previously (14). A dominant T-cell epitope on MSP119 (p24; EPTPNAYYEGVFCSSSS) was synthesized as described previously (13). Ovalbumin (OVA; Sigma, St. Louis, Mo.) was used as a control antigen. Immunization Tyrosine kinase inhibitor and challenge infection Mice were immunized with phosphate-buffered saline (PBS) or MSP119 by using the vaccination protocol described previously (5). Briefly, mice were immunized subcutaneously with PBS or 20 g of MSP119 in complete Freunds adjuvant (CFA) (Sigma). The mice were boosted.