. In patients with hematological malignancies receiving an allogeneic hematopoietic cell transplant (allo-HCT), donor T cells targeting minor histocompatibility antigens play a significant role in both the potentially curative graft-versus leukemia (GVL) response, and in the destructive effects associated with graft-versus-host- disease (GVHD). Identification of novel minor histocompatibility antigens targeted by donor T cells in GVL/GVHD will enable new therapeutic strategies or prognostic genetic tests designed to improve allo-HCT outcomes by promoting GVL responses and/or inhibiting GVHD. However, current techniques to identify minor histocompatibility antigens are time consuming, technically challenging and biased. Only a few minor antigen targets of GVL and GVHD have been identified to date. This study tests a new approach for the rapid identification of minor histocompatibility antigens. The first step in our approach involves large-scale genotyping of coding non-synonymous single nucleotide polymorphisms (coding non- synonymous SNPs). By definition, alternate alleles of each coding non-synonymous SNPs encode alternative amino-acid residues within the encoded protein. We will compare donor and recipient coding non-synonymous SNP genotypes from two HLA-identical, HLA-A*0201 positive allo-HCT donor/recipient pairs. The goal of this comparison is to identify individual alleles that are present in the recipient but not the donor. These alleles precisely define amino-acid polymorphisms unique to the recipient and not their donor. All 9 residue peptides that include one residue that is unique to the recipient are then evaluated by proven class I epitope prediction algorithms. Peptides that are both unique to the recipient and not their corresponding donor, and are predicted to bind the most common human HLA class I allele, HLA-A*0201, are candidate minor histocompatibility epitopes. This process creates a patient-specific list of candidate minor epitopes for each transplant. We will then test T cell responses to these epitopes at diagnosis of acute GVHD using Granzyme B ELISPOT assays. . Relevance to Public Health-The goal of this study is to improve hematopoietic cell transplantation treatments for leukemia. Currently, T cells that are included in the transplant often cause both a severe, potentially deadly autoimmune-like side effect known as GVHD, and a beneficial, potentially curative effect known as """"""""graft-versus-leukemia"""""""" (GVL). We will test a new process to analyze genetic data to identify proteins targeted in both GVHD and GVL responses. Efficient identification of these target proteins will allow development of treatments that will modify transplants to promote the beneficial, curative GVL effect, while minimizing harmful GVHD responses. ? ? ?
