Targeting antigen-specific T cells by genetically engineered antigen presenting cells - A strategy for specific immunotherapy of autoimmune disease

We describe a strategy for specific immunotherapy of autoimmune disease bas ed on targeting the antigen-specific T cells in an experimental model of my asthenia gravis. To address the problem of heterogeneity of the T cell repe rtoire, we have genetically engineered antigen presenting cells (APCs) to p rocess and present epitopes of the autoantigen, acetylcholine receptor (ACh R), to the entire spectrum of AChR-specific syngeneic T cells. APCs derived from BALB/c mice were stably transfected with cDNA for the key immunogenic domain of the AChR alpha-subunit, flanked by sequences of the lysosome-ass ociated membrane protein (LAMP) that direct APCs to process and present the antigen via the MHC Class II pathway. Transfected APCs strongly stimulated AChR-specific T cells from BALB/c mice. Fas ligand, or antibody to Fas, ab rogated the T cell response, by inducing apoptosis of the APC-stimulated T cells. The new results of this investigation are (1) that autoreactive T ce lls can be effectively targeted by autologous APCs that are engineered to p resent the relevant autoantigen, and (2) that these specifically targeted a nd activated T cells can be profoundly inhibited by agents that trigger the Fas-mediated apoptosis pathway. The present findings suggest that engineer ing APCs for simultaneous presentation of the autoantigen and delivery of F asL will provide a powerful strategy for the elimination of autoreactive T cells. (C) 2000 Elsevier Science B.V. All rights reserved.