title: Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4.
abstract: Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: S H
authors.initials: SH
authors.lastname: Im
authors.forename: D
authors.initials: D
authors.lastname: Barchan
authors.forename: P K
authors.initials: PK
authors.lastname: Maiti
authors.forename: S
authors.initials: S
authors.lastname: Fuchs
authors.forename: M C
authors.initials: MC
authors.lastname: Souroujon
mesh_terms: D000069594:Abatacept; D000818:Animals; D000918:Antibody Specificity; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage*; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014101:Torpedo / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D007106:Immune Sera; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D011950:Receptors, Cholinergic; D023201:CD40 Ligand; D000069594:Abatacept