Activation of immune responses against viral infections or tumors depends on a complex interaction of T calls, foreign antigen and antigen-presenting calls. In some cases, the immune response is suboptimal, therefore, efforts towards developing an ideal form of immunotherapy have focussed on enhancing one or more of these immune components. The approach to immunotherapy presented in this study differs from those previously examined in that an attempt will be made to enhance the immune response by augmenting the native ability of T cells to respond to antigen through T cell receptor (TCR)-CD3 complex without invoking alternate efferent or afferent immune mechanisms. It is known that monoclonal antibodies (mAb) recognizing certain T call surface molecules (i.e. TCR, CD3, CD2, etc.) can activate T cells in the absence of nominal antigen. The mAb mimics physiologic antigen and bypasses the antigen-specific recognition mechanism. Our laboratory has developed a monoclonal anti-murine CD3 antibody that reacts with all murine mouse T cells expressing a TCR complex. Although the anti-CD3 mAb functions to suppress immune responses to organ graft recipients as a consequence of T cell depletion and receptor blockade, our studies suggest that the monoclonal antibody can function in vivo as an antigen-independent mitogen capable of activating a variety of T cell functions. In this regard, we have demonstrated that in vivo treatment with low doses of anti-CD3 mAb results in a substantial activation of T cells including IL-2 receptor expression, secretion of lymphokines such as colony stimulating factors, IL-2, and interferon-gamma and rejection of malignant progressor tumors. The proposed studies are designed to: 1) Better understand the mechanism of activation of T calls by mAbs; 2) Develop insights into the mechanism by which anti-CD3 antibodies administered In vivo alter the immune response; 3) Evaluate the role of accessory cells in vivo using heterobifuncional reagents to specifically target the anti-CD3 antibodies to T cells; 4) Exploit the activation properties of anti-CD3 as well as other T cell reagents to modulate immune responses against tumors and viral infections; and 5) Utilize anti-CD3-mediated induction of lymphokines in promoting hematopoiesis.
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