title: A BAFF antagonist suppresses experimental autoimmune encephalomyelitis by targeting cell-mediated and humoral immune responses.
abstract: BAFF [B cell-activating factor of the tumour necrosis factor (TNF) family] and APRIL (a proliferation-inducing ligand) are two TNF family members with shared receptors. While, physiological roles for APRIL are not fully understood, BAFF is critical for B cell homeostasis and also acts as a co-stimulator of T cells. Using a B and T cell-mediated mouse model of multiple sclerosis (MS), myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), we observed that a BAFF/APRIL antagonist (soluble BCMA-Fc) inhibited central nervous system inflammation and demyelination such that it suppressed the onset and progression of clinical symptoms of EAE. In addition to dramatically reducing the titre of MOG-specific auto-antibodies, this treatment also induced a switch in the subtype of the T(h) cell population characterized by marked alterations in cytokine production following re-stimulation with MOG in vitro. Indeed, hBCMA-Fc therapy led to significant increases in the level of transforming growth factor beta, while the levels of T(h)1 cytokines were markedly diminished. These results not only identify BAFF as a critical factor in maintaining humoral immunity in EAE but also support its role in T lymphocyte responses. Our findings demonstrate that hBCMA-Fc acts on both effector arms of the immune response in EAE, a characteristic that may be of significant therapeutic value in the treatment of MS.
authors.affiliation: Neuroimmunology Laboratory, Department of Biochemistry, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.forename: Ryo
authors.initials: R
authors.lastname: Tomioka
authors.forename: Chelsea
authors.initials: C
authors.lastname: Clavarino
authors.forename: Anne M
authors.initials: AM
authors.lastname: Chow
authors.forename: David
authors.initials: D
authors.lastname: Liñares
authors.forename: Paula
authors.initials: P
authors.lastname: Maña
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Cachero
authors.forename: Fang
authors.initials: F
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Kalled
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D053301:B-Cell Maturation Antigen / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage*; D051379:Mice; D016688:Mice, Inbred NOD; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000008:administration & dosage / Q000633:toxicity; D063308:Myelin-Oligodendrocyte Glycoprotein; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D007141:Immunoglobulin Fc Fragments; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011993:Recombinant Fusion Proteins; C490176:Tnfrsf17 protein, mouse; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13