Specific immunotherapy of experimental myasthenia by genetically engineered APCs: the "guided missile" strategy.
Although treatment of MG with general immunosuppressive agents is often effective, it has important drawbacks, including suppression of the immune system as a whole, with the risks of infection and neoplasia, and numerous other adverse side effects. Ideally, treatment of MG should eliminate the specific pathogenic autoimmune response to AChR, without otherwise suppressing the immune system or producing other adverse side effects. Although antibodies to AChR are directly responsible for the loss of AChRs at neuromuscular junctions in MG, the AChR antibody response is T cell-dependent, and immunotherapy directed at T cells can abrogate the autoantibody response, with resulting benefit. As in other autoimmune diseases, the T cell response in MG is highly heterogeneous. The design of specific immunotherapy must take this heterogeneity into account and target the entire repertoire of AChR-specific T cells. We describe our investigation of a novel strategy for specific immunotherapy of MG, involving gene transfer to convert antigen-presenting cells (APCs) to "guided missiles" that target AChR-specific T cells, and that induce apoptosis and elimination of those T cells. This strategy uses the ability of APCs from a given individual to present the entire spectrum of AChR epitopes unique for that individual, and thereby to target the entire repertoire of antigen-specific T cells of the same individual. Using viral vectors, we have genetically engineered the APCs to process and present the most important domain of the AChR molecule, and to express a "warhead" of Fas ligand (FasL) to eliminate the activated AChR-specific T cells with which they interact. Our results show that the APCs express the appropriate gene products, and effectively and specifically eliminate AChR-specific T cells by the Fas/FasL pathway, while sparing T cells of other specificities.
Neuromuscular Laboratory, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287-7519, USA. dandrac@aol.com
D B
DB
Drachman
J-M
JM
Wu
A
A
Miagkov
M A
MA
Williams
R N
RN
Adams
B
B
Wu
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D016923:Cell Death; D002460:Cell Line; D003713:Dendritic Cells; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D007167:Immunotherapy; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000628:therapy* / Q000662:veterinary; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
D011506:Proteins; D011950:Receptors, Cholinergic; D019014:fas Receptor; C018589:lysosomal proteins