The overall goal of this proposal is to develop novel immunotherapeutic strategies for the elimination of specific pathogenic T cells. The central premise of the investigators is that cell based immunotherapies can be devised that are specific and effective. This premise, and the specifics of their approach, are based upon a series of findings relating to the molecular mechanisms of immunoregulation mediated by CD8+ lymphocytes. These findings, based primarily on anti-sense and sense mutagenesis experiments that allow a fine dissection of surface molecular phenotypes, have permitted them to formulate an integrated hypothesis with the following tenets: 1) Immunoregulation can occur through cell:cell contact; 2) Cell surface-associated molecules mediate immunoregulatory signaling in this cellular contact based mode of immunoregulation; 3) Cosignaling is the operative mechanism for this type of immunoregulation (paralleling the well established cosignalling mechanism that is operative in immune cell activation); and 4) In the case of CD8+ immunoregulatory cells, the cosignaling consists of two defined components. One is the specific cell surface associated antigen. The second is the nonspecific cosignal, cell surface associated CD8alpha. This hypothesis defines a new function for CD8alpha.Namely, this well known receptor/adhesion molecule, capable of receiving activating signals, can also function as a ligand molecule, sending inhibitory signals. They now seek to use this property of CD8 to develop novel CD8 based therapies to effect antigen specific immunoregulation. A byproduct of these investigations may be insights into the physiological relevance of antigen-specific CD8-dependent immunoregulation.
Specific Aims #1 and #2 are directed toward the design of engineered CD8alpha polypeptide derivatives that can be used to coat primary antigen presenting cells and that have immunotherapeutic potential.
Specific Aims #3, #4 and #5 are directed toward defining, at a molecular level, the inhibitory mechanisms in target cells undergoing antigen specific CD8 dependent immunoregulation.
Specific Aim #5 seeks to develop animal model systems for the evaluation of antigen specific CD8 dependent immunotherapeutics and mechanisms.
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