Hepatosplenic disease can be a life threatening complication of schistosomiasis. In this regard, we have recently demonstrated the strong association of HLA class II allele DQbeta*0201 with the development of hepatosplenic disease in Brazilian patients. This allele is associated with other diseases with defects in immune regulation, celiac disease and insulin dependent diabetes. We hypothesize that this MHC Class 2 allele influences the priming of T cells leading to a response distinct from individuals with other DQ haplotypcs. Further, analysis of HLA Class 2 alleles and patients immune responses showed a strong association of alleles DQbeta1*0501, DQalpha1*0101 and DR1 with lowered or no response to soluble egg antigens as compared to the total patient population. We propose to compare the in vitro priming response of peripheral blood mononuclear cells (PBMC) to schistosome antigens of individuals carrying these alleles to individuals carrying DQ and DR alleles where no statistical association was shown with disease. The response to schistosome antigens would then be compared to the response from the same individuals to third party antigen such as PPD. We will measure the in vitro priming (IVP) cytokine profiles/proliferation of naive PBMC to schistosome antigens, and then correlate these results with HLA Class II haplotype. Then we will determine if these responses are representative of in vitro responses of HLA Class II matched PBMC from patients prior to, or after development of hepatosplenic disease. We will see if HLA Class II haplotype correlate with expression of MHC class II and co-stimulatory molecules on PBMC after IVP with Schistosome antigens. We will determine whether the IVP response to schistosome antigens can be altered by treatment with exogenous cytokines or anti-cytokine antibodies, and whether the ability to be altered correlates with HLA Class II haplotype. These studies should provide significant new data on the influence of HLA Class II alleles on development and control of cellular immune responses to schistosome antigens and lead to predictive markers for resistance/susceptibility or the likelihood of developing disease.
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