DESIGNER VETO CELLS FOR INDUCTION OF ANTIGEN SPECIFIC TRANSPLANTATION TOLERANCE

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The veto phenomenon has been investigated as a mechanism for the indution of antigen specific transplantation tolerance since the mid- 1980's. The veto phenomenon involves an interaction between an allospecific T cell that recognizes foreign MHC antigen on the surface of an antigen presenting cell (APC) and the APC: on engagement of MHC alloantigen by the T cell, the APC delivers a negative signal to the T cell. Thus, the APC has veto activity because it abrogates the activation of the T cell which would destroy it. Although the veto phenomenon is most efficiently mediated by highly active cytotoxic T lymphocytes (CTL) clones, veto activity is not highly reproducible in vivo, especially when there is a strong MHC disparity between host and donor. To engineer the veto phenomenon to be highly efficient and effective, we constructed MHC hybrid molecules which, when expressed by CTL, redirect the lytic capability of the cell to destroy allospecific T cells. To do so, the extracellular domains of an MHC class I (D of d) molecule were fused to the intracellular domains of the TcR associated zeta chain, which serves as a ~highly efficienct signal transduction molecule. Recognition and engagement of the MHC class I p~rtion of the molecule by allospecific T cells should trigger the activity and lytic function of CTL expressing these constructs, much as would occur via engagement of their clonotypic TcRs. These hybrid molecules have been transfected into human Jurkat lines to test for their signalling capacity and will be transfected into CTL hybridomas to assess the ability to trigger lytic activity. Additionally, transgenic mice are being constructed such ~hat key effector populations can be cloned directly from the animal and for use in transplantation studies.