Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes.
We demonstrate here the feasibility of antigen-specifically redirecting T cells against autoreactive T lymphocytes and thereby treating a model autoimmune disease. We created and transgenically expressed on T cells a heterodimeric chimeric receptor that genetically links an autoantigenic peptide, its restricting MHC, and the signal transduction domain of the T-cell receptor (TCR) zeta-chain. Engagement of the chimeric receptor by the TCR of autoreactive T cells activated the receptor-modified T cells in vitro and in vivo, inducing proliferation and cytolysis. Adoptively transferred receptor-modified T cells prevented and treated a model autoimmune disease, experimental allergic encephalomyelitis (EAE), even after epitope spreading had diversified the autoantigenic response. Treatment reduced disease severity and increased survival of affected animals, and was durable for >75 days. The receptor-modified cells acted both by strongly attenuating T-cell response to autoantigen as well as by shifting the residual response from an immunopathologic Th1 to a protective Th2 format.
Jyothi
M Divya
MD
Department of Pathology, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105, USA.
Flavell
Richard A
RA
Geiger
Terrence L
TL
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000628:therapy; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D005240:Feasibility Studies; D005260:Female; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D007116:Immunization, Passive / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013491:Suppressor Factors, Immunologic / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell; D013491:Suppressor Factors, Immunologic