Autoreactive T lymphocytes (ATL) are critical regulatory and effector cells for rheumatoid arthritis and other autoimmune diseases. Eradication of these ATL may ameliorate or cure such diseases. Therapies capable of selectively targeting ATL are not available clinically. This proposal describes the develpment of a novel therapy that uses genetically modified T lymphocytes (GM-TL) to selectively eliminate ATL. The GM-TL will be transfected with a chimeric receptor capable of both recognizing ATL and activating the GM-TL. This receptor consists of- a. class II major histocompatability complex (MHC alpha and beta chains, b. covalently linked autoantigenic peptide, and c. activation domain derived from the T cell receptor complex. The ATL T cell receptor will specifically interact with the MHC-peptide complex of the chimeric receptor. This interaction will activate the GM-TL, which in turn will kill or downmodulate the ATL. By using GM-TL to selectively eliminate ATL it should be possible to modulate or abrogate ongoing autoimmune disease. This will be tested using a well characterized murine model for autoimmune arthritis, collagen induced arthritis (CIA). Chimeric construct design will be optimized using in vitro and in-vivo assays of GM-TL activity. These analyses will examine the capacity of GM-TL to kill or modulate the reactivities of type II collagen specific T lymphocytes. GM-TL will then be adoptively transferred into mice prior to, concurrent with, or following the induction of CIA. Pathologic and clinical measures of outcome will be assessed. These experiments will thus provide the initial studies assessing the usefulness of GM-TL in treating autoimmune arthritis. It will establish a precedent for the analagous use of GM-TL as a therapy for human autoimmune disease.
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