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Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717
Anti-inflammation immunotherapy has been successfully applied for the treatment of autoimmune diseases. Mucosal vaccines against autoimmune disorders are beneficial by influencing the regulatory compartment of gut and systemic adaptive immune systems. A Salmonella vector expressing colonization factor Ag I (CFA/I), shown to behave as an anti-inflammatory vaccine, stimulates the production of CD4+CD25+ T cells and regulatory cytokines. In this work, we queried whether Salmonella-CFA/I can protect DBA/1 mice from collagen-induced arthritis. The incidence of arthritis and cartilage loss in vaccinated DBA/1 mice was remarkably lower when compared with unprotected mice. Clinical findings were accompanied by the suppression of inflammatory cytokines TNF-
, IL-1β, IL-6, and IL-27. Vaccination evoked a multi-tier response consisting of IL-4 producing Th2 cells, an increased production of TGF-β by CD4+ T cells, and suppression of collagen II-specific CD4+ T cell proliferation. To assess the contribution of Salmonella-CFA/I-primed CD4+ T cells, adoptive transfer studies with total CD4+, CD4+CD25–, or CD4+CD25+ T cells were performed 15 days postchallenge. Mice receiving either subset showed reduced disease incidence and low clinical scores; however, mice receiving total CD4+ T cells showed delayed disease onset by 10 days with reduced clinical scores, reduced IL-17 and IL-27, but enhanced IL-4, IL-10, IL-13, and TGF-β. Inhibition of TGF-β or IL-4 compromised protective immunity. These data show that Salmonella-CFA/I vaccination of DBA/1 mice protects against collagen-induced arthritis by stimulating TGF-β- and IL-4-producing regulatory CD4+ T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by U.S. Public Health Service Grant AT-04312 and AI-41123 and in part by Montana Agricultural Station and U.S. Department of Agriculture Formula Funds. The VMB flow cytometry facility was, in part, supported by National Institutes of Health/National Center for Research Resources, Centers of Biomedical Excellence P20 RR-020185, and an equipment grant from the M. J. Murdock Charitable Trust.
2 Address correspondence and reprint requests to Dr. David W. Pascual, Veterinary Molecular Biology, Montana State University, P.O. Box 173610, Bozeman, MT 59717-3610. E-mail address: dpascual{at}montana.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; CII, collagen II; ETEC, enterotoxigenic E. coli; CFA/I, colonization factor Ag I; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; Treg, regulatory T cell; LN, lymph node; CFC, cytokine-forming cell; MLN, mesenteric LN; HNLN, head and neck LN; GITR, glucocorticoid-induced TNF receptor.
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