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 based on targeting the antigen-specific T cells in an experimental model of myasthenia gravis. To address the problem of heterogeneity of the T cell repertoire, we have genetically engineered antigen presenting cells (APCs) to process and present epitopes of the autoantigen, acetylcholine receptor (AChR), 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-associated 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, abrogated the T cell response, by inducing apoptosis of the APC-stimulated T cells. The new results of this investigation are (1) that autoreactive T cells can be effectively targeted by autologous APCs that are engineered to present the relevant autoantigen, and (2) that these specifically targeted and activated T cells can be profoundly inhibited by agents that trigger the Fas-mediated apoptosis pathway. The present findings suggest that engineering APCs for simultaneous presentation of the autoantigen and delivery of FasL will provide a powerful strategy for the elimination of autoreactive T cells.
Wu
J M
JM
Department of Neurology, Johns Hopkins School of Medicine, 5-119 Meyer Building, 600 N. Wolfe St., Baltimore, MD 21287-7519, USA.
Wu
B
B
Guarnieri
F
F
August
J T
JT
Drachman
D B
DB
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000502:physiology*; D001327:Autoimmune Diseases / Q000628:therapy*; D000939:Epitopes; D053222:Fas Ligand Protein; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D005818:Genetic Engineering; D007167:Immunotherapy / Q000379:methods*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D000906:Antibodies; D000939:Epitopes; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor