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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900747v1 183/10/6041    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Ochoa-Repáraz, J. Articles by Kasper, L. H. PubMed PubMed Citation Articles by Ochoa-Repáraz, J. Articles by Kasper, L. H.

Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis¹

Javier Ochoa-Repáraz,^2* Daniel W. Mielcarz, Lauren E. Ditrio, Ashley R. Burroughs, David M. Foureau, Sakhina Haque-Begum,^* and Lloyd H. Kasper^*

^*Department of Medicine and Departments of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756

Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gut commensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed no significant decline in the gut microflora and developed EAE similar to untreated mice, suggesting that reduction in disease activity was related to alterations in the gut bacterial population. Protection was associated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptive transfer of low numbers of IL-10-producing CD25⁺CD4⁺ T cells (>75% FoxP3⁺) purified from cervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25⁺ cells suggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our data demonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immune tolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions.

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 the Dartmouth-Hitchcock Foundation (to J.O.-R.; Tiffany Blake Fellowship 205-702B) and by training grants from TEVA Neuroscience (to L.H.K.; Grant 50-2033, TEVA Neuroscience Murray B. Bornstein Fund) and the National Multiple Sclerosis Society (to L.H.K; Grant CA1027A1/3).

² Address correspondence and reprint requests to Dr. Javier Ochoa-Repáraz, Department of Medicine, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address: javier.ochoa-reparaz{at}dartmouth.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; CLN, cervical lymph node; DC, dendritic cell; MLN, mesenteric lymph node; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PLP, proteolipid protein; PP, Peyer’s patches; PT, Bordetella pertussis toxin; RA, retinoic acid; T_reg cell, regulatory T cell.

⁴ The online version of this article contains supplemental material.