): Bone marrow transplantation (BMT) is an accepted form of therapy for various hematologic and malignant diseases. The most important complication following allogeneic BMT is the development of graft versus host disease (GVHD). The incidence and severity of GVHD has increased, due to current protocols of BMT, using unrelated HLA matched donors from the registry. GVHD in HLA matched BMT is considered to be due to mismatches in minor histocompatibility antigens (mH) between the donor and recipient. Current information about the mH antigens involved in GVHD in humans and animals are limited. The overall goal of this proposal is to cellularly and molecularly define mH antigens involved in the development of CD4 mediated GVHD in a murine BMT model and to develop and characterize cells involved in the pathogenesis of GVHD in human allogeneic HLA matched BMT. The candidate will isolate and clone CD4+ T cells from mouse BMT recipients undergoing GVHD in an mH disparate combination. The T cell clones will be characterized with regard to their specificity using proliferative as well as cytotoxic methods. T cell clones recognizing mH antigens will be used to identify, isolate and sequence mH peptides recognized by the CD4+ T cells. MHC molecules with bound peptides will be isolated from recipient strain splenocytes. Peptides will be eluted using trifluoroacetic acid, and peptide fractions from reversed phase high profile liquid chromatography will be used for sensitization of appropriate MHC expressing target cells. Sensitizing fractions will be sequenced to define the motif and to determine the protein origin of the mH antigen involved in GVHD in this mouse model. T cell lines, and both CD8 as well as CD4 clones, will be developed from BMT patients undergoing GVHD following allogeneic HLA matched BMT. T cell lines developed from patients undergoing GVHD at different times post BMT will be studied for their T cell repertoire using spectratyping technique in order to determine the dominance of TCR phenotypes and thus dominance of certain mH antigens. T cell clones developed will be analyzed for their mH antigen tissue specificity, HLA allele restriction, and polymorphism within the population. The long-term goal of this proposal is to define mH peptides involved in human GVHD following allogeneic BMT in order to formulate approaches in preventing and treating GVHD in humans.
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