Human Minor Histocompatibility Antigens

次要组织相容性抗原（mHA）是由主要组织相容性复合体（MHC） I类和II类分子呈现的正常细胞蛋白衍生的肽。当供体与所有MHC等位基因匹配时，供体T细胞对mH的识别在很大程度上有助于同种异体造血干细胞（HSC）移植后的移植物抗宿主病（GVHD）。到目前为止，人类mHA仅通过确定MHC中结合的肽的氨基酸序列来鉴定，这些肽被同种异体反应性T细胞克隆特异性识别。这导致了几种MHC i类限制性和ii类限制性mHA的鉴定，并证明T细胞免疫原性依赖于这些肽内或邻近区域中单个氨基酸取代的存在。这些氨基酸取代是由区分受体的单核苷酸多态性（SNP）引起的

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.