Hematopoietic stem cell transplantation (HSCT) has become life saving therapy for patients with various congenital, acquired and malignant diseases of the immune and hematopoietic systems. Graft rejection, graft-versus-host disease (GVHD) and prolonged immune deficiency remain significant causes of morbidity and mortality. The overall theme of this Program Project grant is to understand alloimmunity and how T cells and natural killer cells interact with alloantigen. Studies in this Program Project are focused on the genomics and function of the human major histocompatability complex (MHC), on genetic matching for transplantation and the definition of optimal criteria for donor selection, on the identification of minor histocompatability (mHA) that function as peptide ligands for alloreactive T cells, and on the development of new strategies for inducing immunological tolerance to alloantigen. Availability of a suitably matched donor has been a significant factor limiting access to clinical HCT. The development of large files of HLA typed volunteer donors, now numbering more than five million worldwide, has greatly improved the therapeutic options of many patients, but more detailed criteria for optimal matching and improved methods for modulating alloimmunity in patients with mismatched grafts are urgently needed. Due to the extreme nature of HLA polymorphism and the significant allograft reactions caused by disparities for mHA, improved genetic matching and larger donor registries alone will not solve the problem for all patients. Successful management of these problems will depend on improving our understanding of alloimmune responses and development of new strategies for achieving tolerance. There are four scientific projects in this Program Project and two administrative and shared resource core components. Project 1 is aimed at a comprehensive analysis of the human MHC and discovery of single nucleotide polymorphism (SNPs). An HLA SNP data set has broad implications for genetic analysis, the study of HLA and disease associations and donor recipient matching. Project 2 is aimed at developing adoptive immune-therapy employing lymphoid dendritic cells (DC) to induce tolerance. Project 3 is aimed at analyzing T cell alloreactivity in HCT recipients and identification of the genetic determinants most relevant to favorable transplant outcome. Core A provides administrative support and shared resources, including biostatistic consultation and a cell bank containing reference materials and donorrecipient cells for analysis of genetic matching and transplant outcome.
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