Minor histocompatibility antigens (mHA) are peptides derived from normal cellular proteins presented by major histocompatibility complex (MHC) class I and class II molecules. Recognition of mH by donor T cells contributes substantially to graft-vs-host disease (GVHD) following transplantation of allogeneic hematopoietic stem cells (HSC) when donors are matched for all MHC alleles. Thus far, human mHA have been identified only by determining the amino acid sequence of peptides bound in MHC that are specifically recognized by allo-reactive T cell clones. This has resulted in the identification of several MHC class I-restricted and class II-restricted mHA and the demonstration that T cell immunogenicity is dependent on the presence of single amino acid substitutions within these peptides or in adjacent regions. These amino acid substitutions result from single nucleotide polymorphisms (SNP) that distinguish recipient from donor but do not generally affect the function of the protein containing the substituted amino acid. Despite many improvements in T cell cloning techniques and peptide sequencing, there are many obstacles to the identification of mHA by T cell clones and this has limited the ability to identify mHA that contribute to GVHD. Preliminary data presented in this application demonstrate that patients also develop antibody responses that specifically recognize mHA after HSCT. This observation suggests that patient serum can be used to identify novel mHA and to determine which mHA are immunogenic in patients with GVHD. Previously, the characterization of MHC antigens was greatly facilitated by the demonstration that serum of multiparous females contained high titer antibodies to specific HLA alleles. Serologic HLA typing enabled successful hone marrow transplantation and advanced our knowledge of MHC structure and function long before MHC DNA sequence determination was possible. The overall goal of this project is to establish whether serologic responses to mHA reflect a coordinated immune response to these antigens after allogeneic HSCT and whether antibody responses can enhance our ability to identify additional mHA.
The specific aims of this project are as follows: 1) Characterize specific antibody responses to known mHA. 2) Determine if antibody responses to known mHA correlate with the development of T cell responses to these antigens. 3) Identify novel mHA by serologic detection with serum from patients with GVHD. 4) Determine if antibody responses to novel mHA correlate with the development of T cell responses to these antigens.
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