The major threat to long term survival of allografts is chronic humoral rejection. In both cardiac and renal transplantation, chronic rejection appears to be induced by HLA antigens since the development of antibodies to donor HLA antigens is associated with graft failure. The recipient's HLA class II genotype may play a major role in the initiation of chronic allograft rejection since class II MHC molecules differ in their ability to bind different antigenic peptides and therefore to stimulate specific helper T cells. In addition, MHC molecules may also play a role in MHC linked immune responsiveness by shaping the repertoire of antigen- responsive T cells through positive and negative selection in the thymus. The overall goal of this proposal is to study the influence of HLA molecules on the alloimmune response.
In Specific Aim 1, the possibility that particular MHC class II genes are associated with responsiveness or nonresponsiveness to alloantigens will be explored. The transplant patient's HLA class II genotype will be established using molecular typing methods. Correlation between the presence or absence of a particular HLA allele and recipient race, production of anti-HLA antibodies, number of rejection episodes and graft survival will be determined. This study will permit the identification of HLA class II alleles associated with immune responsiveness to the graft.
Specific Aim 2, is to determine whether HLA class I and II molecules influence the selection of the peripheral TCR repertoire within the CD8+ and CD4+ compartments. The peripheral repertoire of CD4+ and CD8+ TCR Vbeta genes will be determined by quantitative PCR and flow cytometric methods in HLA-identical siblings and in parents and siblings who differ by one and/or two haplotypes. If a similar frequency of TCR Vbeta genes in HLA- identical siblings compared to one or two haplotype mismatched siblings is found, this would indicate that MHC guides the selection of TCR V genes. The influence of class I and class II genes in shaping the CD4 and CD8 TCR repertoire will be analyzed in HLA-B/DR cross-over families. The possible relationship between the individual's HLA-DR genotype and the frequency of particular Vbeta genes within the CD4 compartment will be explored in families with intercrosses for particular HLA-DRB alleles.
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