Genetics of Graft-Versus-Host Disease

Abstract SCI-49

The HLA barrier remains the primary roadblock to hematopoietic cell transplantation from alternative donors for the treatment of blood disorders. Currently over 18 million unrelated donors are represented by registries worldwide and they serve as a critically important resource for patients in need of a transplant. The basis for the selection of unrelated donors has evolved with advances in HLA typing technology. The demonstration that serologically identical HLA phenotypes have DNA-defined allelic variants that can provoke graft-versus-host reactions has served as the basis for the current criteria for the selection of donors. Although donor HLA matching lowers morbidity and mortality from graft-versus-host disease (GVHD), matching does not guarantee that the patient will not experience life-threatening GVHD and require prolonged immunosuppression after transplantation. Furthermore, the risks of acute and chronic GVHD associated with transplantation from HLA mismatched donors has lead to a reluctance to use mismatched donors for some patients. In 2011, the unmet need is two-fold. First, the vast majority of patients in need of a transplant have no HLA matched unrelated donor. To permit these patients the opportunity for a life-saving transplant, more information on the rules that govern permissible donor-recipient HLA mismatches is needed. Second, information is needed on the extent of non-HLA genetic variation that resides within the major histocompatibility complex (MHC) region and the manner in which such variation contributes to the transplantation barrier. Several research strategies have been applied to identify HLA mismatch combinations that can be used safely, including but not limited to analysis of individual amino acid residues that define the peptide binding repertoire of HLA class I and II alleles and antigens, and computational approaches that relate the sequence to structure of HLA molecules. The availability of a dense map of over 36,000 single nucleotide polymorphisms and complete sequence information for common HLA haplotypes has recently provided new information on the extent of human genetic variation and its organization on haplotypes. These data serve as a rich resource for mapping novel MHC resident variation associated with GVHD risk and transplant outcome. New information is emerging on the diversity of the MHC among transplant patient-donor pairs, the organization of simple and complex genetic variation relative to the classical HLA loci, and the putative regions within the MHC that are amenable to fine mapping. Future investigation of the genetic basis of GVHD will be enhanced with more complete information on MHC region variation in diverse human populations, haplotype content, and robust tools for both querying and analyzing complex variation.