GENETIC CONTROL OF HLA CLASS I ALLOANTIBODY RESPONSES

点击翻译按钮获取中文摘要

The objectives of this proposal are to define the molecular and the cellular mechanisms that control a person's ability to produce an HLA antibody response against the Class I histocompatibility antigens. Our ultimate goal will be to provide a scientific basis for beginning to devise innovative strategies to minimize or eliminate the induction of a humoral HLA response. These investigations hinge on the hypothesis that immune regulation is dictated primarily through the classical mechanism of immune response (Ir) genes, controlled primarily by the ability of the host's HLA Class II antigens to bind and present foreign HLA allopeptide to CD4+ T lymphocytes (helper cells). HLA alloantibody formation is then initiated through cooperative interactions between these activated T lymphocytes in concert with B lymphocytes that possess the appropriate immunoglobulin receptors and Ir gene products. There are three specific aims to this proposal. The first is to map the patterns of HLA Class II antigen restriction using a library of synthetic HLA Class I peptides representing polymorphic domains of two major families of HLA antigens, HLA-A2 and HLA-B7. Direct peptide binding assays with viable cells will be performed using analytical flow cytometry. The second aim will be to determine whether these Ir genes correlate in vivo with the capacity to produce specific HLA alloantibody and whether these factors contribute to chronic vasculopathy of the allograft and ultimately, graft failure. Collaborative studies with other centers and with an international transplant registry have been organized for this purpose. The third aim will be to confirm by in vitro methods that cognitive interactions between peptide-specific CD4+ T helper cells occur through allorecognition of HLA Class I peptides presented by B lymphocytes. The potential clinical significance of these findings in the field of organ transplantation is of considerable magnitude. First, understanding what dictates both HLA immunogenicity and the controlling factors or rules that regulate antibody responses could eventually be applied to identify transplant candidates who are at risk to produce HLA antibody against a particular foreign allograft ("responder phenotype"). Second, complementary to this, new strategies for molecular matching could be applied for patients who are identified a priori as possessing the responder phenotype. Third, with reduction or elimination of the humoral effector circuit using these strategies, it may be feasible to customize an individual's immunosuppressive medications based on the type and the degree of HLA antigen mismatch and/or to devise strategies for induction of T cell anergy or tolerance to the donor allograft. Most important, avoidance of humoral sensitization could reduce the rate of transplant rejection and the corresponding economic drain associated with graft failure and the ensuing costs accompanying chronic medical care.