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. This study proposes to test the use of tiling arrays to identify novel minor antigens determined by coding deletion polymorphisms. Since this type of polymorphism is likely to present donor T-cells with multiple foreign epitopes, they may represent a particularly potent subclass of clinically useful minor antigens. We propose to genotype HLA-matched, unrelated allogeneic hematopoietic cell transplant donor/recipient pairs for disparities in coding deletion polymorphisms. We will then test for T-cell responses against proteins encoded within donor-restricted deletion polymorphisms following diagnosis of GVHD using ELISPOT assays. The identification of novel minor antigens determined by deletion polymorphisms will represent a significant step towards enabling individualized genomics- based prognostic tests for GVL/GVHD, and improved transplantation protocols designed to specifically promote the therapeutic GVL response. ? ?
The long term goal of this study is to improve hematopoietic cell transplantation treatments for leukemia. However, if successful, this approach may also lead to significant improvements in solid organ transplantation as well. Currently, mature T cells included in an allogeneic stem cell 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 genetic approach to identify proteins targeted in both GVHD and GVL responses. Efficient identification of these target proteins will allow development of prognostic tests, and modification of transplant protocols to specifically promote the beneficial, curative GVL effect. ? ? ?
