Tr1 cell-dependent active tolerance blunts the pathogenic effects of determinant spreading.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. The current study shows that even in an acute episode of disease the autoimmune response spreads from one determinant on myelin basic protein (MBP) to the other linked determinant and that this spread plays a functional role in the pathogenesis of disease. The soluble form of each determinant could be used to induce Ag-specific T cell tolerance and reverse an ongoing disease. We show that the rapid effect of soluble peptide therapy is due to repolarization of autoimmune T cells undergoing activation. We suggest that at least two different types of regulatory T cells participate in the induction of active tolerance. The first, yet to be fully characterized, functions in an IL-4-dependent manner. The second produces high levels of IL-10 and low levels of IL-4 (Tr1). We bring about completing evidence showing that these Tr1 cells play a pivotal role in the regulation of T cell tolerance during determinant spread and that soluble peptide therapy with the determinant to which the autoimmune response spreads amplifies a de novo regulatory mechanism aimed to reduce the pathological consequences of determinant spreading.
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Gizi
G
Wildbaum
Nir
N
Netzer
Nathan
N
Karin
D000818:Animals; D000941:Antigens / Q000737:chemistry; D002455:Cell Division; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D010455:Peptides / Q000737:chemistry; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D000941:Antigens; D016207:Cytokines; D010455:Peptides; D016753:Interleukin-10; D015847:Interleukin-4