Minor histocompatibility antigens (mHA) are peptides derived from normal cellular proteins that are presented by major histocompatibility antigen (MHC) class I and class H molecules. Identification of individual human mHAs has focused on physically isolating and determining the amino acid sequence of peptides bound in MHC with only five mHA epitopes determined thus far. It is generally believed that a more extensive assessment of mHA will lead to improvements in the typing of donors and recipients undergoing allogeneic hematopoietic stem cell (HSC) transplantation and a decreased rate of graft versus host disease (GVHD). Allogeneic transplantation was initially facilitated by employing serum of multiparous females to human leukocyte antigen (HLA) type individuals. I have developed preliminary evidence that HSC transplant patients develop humoral responses to well characterized H-Y antigens and autosomal mHA. This suggests that GVHD patient serum can be used to identify novel mHA, and to rapidly enhance our ability to determine which of these antigens contribute to GVHD. HYPOTHESIS: The immunogenicity of minor histocompatibility antigens (nfflAs) results in a coordinated response involving both T and B-cell immunity to the target antigen, and therefore, genes encoding mHA can be identified by serologic detection of an expression library with GVHD patient serum. Within these candidate genes, the mHA epitope is defined by a single nucleotide polymorphism (SNP). To address this hypothesis, Dr. Miklos plans to accomplish the following aims: 1) Characterize specific antibody responses to H-Y antigens in male recipients of female HSC transplants with an ELISA panel of UTY, SMCY, DBY, and ElFlAY, as well as autosomal mHA HA-1 and HA-8. 2) Determine if serologic response to H-Y antigen can be detected in female blood donors, and if serologic detection of H-Y antigens in allogeneic HSC donors correlates with subsequent development of GVHD in male HSC transplant recipients. 3) Identify novel mHA by utilizing the SEREX method to screen a phage expression library with GVHD patient serum, and then identify single nucleotide polymorphisms (SNPs) encoding potential mHA epitopes that differ between SEREX positive donor and recipient. Finally, SNP disparity will be determined in association with GVHD to confirm mHA. Dr. Miklos' research will be performed in the laboratory of Dr. Jerome Ritz, a leader in the field of immunology and allogeneic HSC transplantation at the Dana-Farber Cancer Institute.
| Nakasone, Hideki; Sahaf, Bita; Tian, Lu et al. (2016) Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes. Haematologica 101:e30-3 |
| Popli, Rakesh; Sahaf, Bita; Nakasone, Hideki et al. (2014) Clinical impact of H-Y alloimmunity. Immunol Res 58:249-58 |
| Miklos, David B; Kim, Haesook T; Miller, Katherine H et al. (2005) Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 105:2973-8 |
