CONSTRUCTION OF FUSION MOLECULES FOR REDIRECTING IMMUNE RESPONSES

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Treatment of HIV infected patients with killer cells expressing a novel fusion molecule (CD4-Zeta) to target and kill HIV infected cells is underway. Although there are no small animal models of HIV to assess the safety and efficacy of such cells, the T cells responsible for graft rejection and autoimmunity may be similarly targeted by killer cells expressing fusion molecules consisting of the extracellular portion of MHC and the signaling molecule zeta of the TcR. We have constructed MHC-zeta fusion molecules and developed an animal model in which to test them. We found that fusion of a signaling molecule to MHC allowed enhanced expression of T cell functions, both helper and killer following cellular recognition or antibody ligation. However, the ability of such cells to eliminate allospecific lymphocytes that recognize such molecules is unclear and being pursued. We further found that infusion of lymphocytes expressing such constructs into normal mice not only is well tolerated, but also prolongs survival of allografts expressing the identical MHC as in the construct, a finding which does not necessarily pertain to veto activity but to the lack of expression of the transgeneon "professional" antigen presenting cells. The CD4-zeta fusion molecule is under active clinical investigation. This program gives the Center the expertise to assess critical issues relating to the manufacture, safety,and efficacy of such constructs. Thus, issues of activation during the selection process by cross linking of ligand with mAb and the subsequent effects on infusion into patients can be assessed. Further, the development of lymphoma in a relatively large percentage of mice expressing this construct has alerted us to some previously unknown safety issues. This program also anticipates the use of a potential new class of biological agents for treatment of transplantation rejection and autoimmunity.