The goal of this project is to define the alloimmune response in patients receiving hematopoietic stem cell transplants (HSCT) from normal donors. The objectives are to identify the alloantigens recognized by host-reactive cytotoxic T cells (CTL) following transplantation and define their role in determining clinical outcome. Matching for antigens of the HLA system reduces the risk of graft rejection, GVHD and mortality. Significant GVHD often occurs, however, in transplants between HLA genotypically identical siblings, demonstrating that clinically relevant in vivo alloimmune responses are caused by determinants other than classical HLA antigens. These antigens, encoded by genes throughout the genome, are termed minor histocompatability antigens (mHA). The peptides identified by mHA specific T cells are largely unknown. Within any individual the response to mHA is constrained by the ability of the immune system to process, select and present specific peptides. The individual's HLA genotype and the presence of an HLA allele to which mHA peptides can bind determine presentation of available peptides. In the studies proposed here the alloimmune response in HSCT recipients will be examined to determine the extent of the reaction to mHA and the diversity of the responding donor's T cell repertoire. The primary hypothesis to be tested is that certain alloantigens function as immunodominant determinants.
The specific aims of this project are to: i) characterize the anti-host T cell response in patients with GVHD, and identify host-reactive T cells and CTL clones associated with GVHD; ii) define the repertoire of HLA-A*O20l-restricted mHA recognized by CTL following HSCT; iii) estimate the number of unique mHAs that can be recognized in individual patients and determine if the same mHA can be recognized in more than one patient; and iv) characterize the immune response to HA-l and define its role in transplantation. We anticipate that a significant number of GVHD-associated T cell clones identifying unique mHA will be isolated during these studies. These will be used to map the genes encoding these clinically relevant mHA through collaboration with the mHA project of the 13th International Histocompatability Working Group (IHWG). The combined data of the IHWG project will allow a comparison of mHA identified in different laboratories, provide a cataloging of unique specificities and generate linkage data essential for the eventual cloning of mHA genes. A better understanding of the alloimmune reactions occurring in HCT patients may also provide insight and rationale for new approaches to preventing GVHD and facilitating tolerance.
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