Tolerance induction by blockade of the immune response at the effector stage will be compared to blockade of the immune response at the stage of antigen presentation. In addition the potential synergism of the two blockades acting at the priming and effector stage, respectively, for restoring or maintaining tolerance will be evaluated. To block effector CTL we will use reagents that trigger CD30 signals on activated T cells in vivo. Both anti murine CD30 antibodies and soluble CD30-Ligand will be used to elicit CD30 signaling. Antigen presentation will be blocked with CTLA4-Ig. A combination of CD30-signaling with CTLA4-Ig will be evaluated and is expected to be synergistic, because different cell populations and molecular mechanisms are addressed by the two pathways. Induction of an immune response will be achieved by a tumor secreted heat shock protein, gp96-1g. Secreted gp96-Ig with its associated peptides induces a tumor rejecting CD8 CTL response in syngeneic B6 mice without the need of CD4 help. Gp96-Ig is able to bind to CD91 on dendritic cells (D.C.) and. activate them without the need for CD40-L. Gp96-Ig associated peptides after uptake by D.C. are presented by class I MHC and activate CD8 cells directly without CD4 help. We postulate that heat shock proteins contribute greatly to all immune responses that have resulted in cell lysis or were caused by cell damage. Therefore methods to induce tolerance to a heat shock protein mediated responses are relevant in many clinical situations. The second in vivo model for restoration of tolerance makes use of tumor rejection mediated by disparate minor transplantation antigens in the presence of identical MHC antigens. In both models the immune response and tolerance induction will be monitored by the expansion of adoptively transferred TCR transgenic CD8 and CD4 cells in addition to the biological readout or tumor growth (tolerance) or rejection (immune response).
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