) Allogeneic bone marrow transplantation (BMT) has emerged as the preferred therapy for a variety of disorders. Unfortunately, outcome is limited by development of graft-versus-host disease (GvHD) and by opportunistic infection. Of the factors that contribute to the increased frequency and severity of GvHD occurring after unrelated donor BMT, genotypic matching for HLA-DRB1 and HLA-DQB1 appear to be particularly important. While the present modalities used to prevent GvHD are of benefit, they are not selective in their effects on the immune system, in that responses to opportunistic pathogens are blunted along with the GVH response. Given the importance of HLA class II allodisparities in initiating GVH responses, one of the logical targets for the development of new immune suppressive agents is the CD4 molecule, which plays a critical role in the activation of CD4+ T cells in response to HLA-class II allodisparities. A variety of structural analogs of portions of the CD4 molecule have been developed which are efficacious, nontoxic, and (at least) additive in immunosuppressive activity to Cyclosporine. One cyclic heptapeptide, 802-2, is now ready for clinical investigation. This peptide requires only short term administration and is selectively active, in that T cells which encounter antigen in the presence of peptide are affected, while T cells which do not encounter antigen until after peptide has been cleared appear to remain functionally intact. This project builds on the previous observations through two specific aims. First, in collaboration with the National Marrow Donor Program, we will begin clinical testing of 802-2 peptide in prevention of GvHD in unrelated donor BMT through phase I and II clinical trials. Second, a variety of immunologic studies are proposed using cells from the donor-recipient pairs participating in the trial to further characterize the in vivo and in vitro effects of 802-2 peptide in man. The composite information gained should allow assessment of the efficacy of the present generation of CD4 analogs and facilitate the design and testing of next generation products. Ultimately this information should help improve outcome for recipients of unrelated donor BMT and reduce or eliminate the immunogenetic barrier which presently excludes at least a third of otherwise appropriate candidates from allogeneic transplantation.
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