) Graft-versus-host disease (GvHD) is a major complication of allogeneic bone marrow transplantation (BMT). The risk of GvHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, only about 30% of patients have a HLA-matched sibling, and thus must seek suitable unrelated HLA-matched donors through the National Marrow Donor Program (NMDP). The risk of GvHD is still quite high in unrelated HLA-matched patients, particularly due to genetic variants in MHC class II loci, whose products can induce CD4+ T cell responses. The prevention of marrow graft rejection is also a critical issue for allogeneic BMT, particularly when involving MHC class II mismatches. As part of this Program, we have focused our attention on the preclinical investigation of structure-base designed peptides and organic compounds that inhibit CD4+ T cell-mediated alloreactivity. We will concentrate our efforts on three groups of inhibitors: (1) the D1 CC' loop peptide (802-2), the lead compound for the current clinical trial; (2) new peptides designed to inhibit dimerization of CD4 molecules in the D4 domain; and (3) two organic compounds (TJU103, and TJU104) that were selected for their ability to block a putative binding pocket on the D1 domain. The BMT models that we will utilize include: (1) the MHC haploidentical B6D2->B6CB (950 cGy) and minor histocompatibility antigen (HA)-mismatched B6 ->BALB.B (850 cGy) models of GvHD; and 2) the MHC haploidentical B6CB ATBM->B6D2 (750 cGy), MHC Class II-disparate Bm12 ATBM->B6.Ly5.2 (700 cGy), and the CD4-Class II-restricted minor HA-disparate BALB.B ATBM->B6 (700 cGy) presensitized models of allogeneic marrow graft rejection. With the selected peptides and compounds in these models, our specific aims are: 1) to determine the efficacy of the 802-2, CD4 D4, and organic inhibitory agents in the GvHD and marrow graft rejection models; (2) to determine mechanism of action of the inhibitory agents; and (3) to evaluate the immunocompetent status of BMT recipients in the GvHD models after treatment with the inhibitory agents. These studies will provide a strong preclinical basis for these novel CD4 inhibitors that could potentially target alloreactive cells without jeopardizing later immune responses to infection and leukemia.
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