HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) 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 Scott, G. N. Articles by Mandik-Nayak, L. PubMed PubMed Citation Articles by Scott, G. N. Articles by Mandik-Nayak, L.

The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity¹

Grant N. Scott^*, James DuHadaway^*, Elizabeth Pigott^*, Natalie Ridge^*,, George C. Prendergast^*, Alexander J. Muller^* and Laura Mandik-Nayak^2,*

^* The Lankenau Institute for Medical Research, Wynnewood, PA 19096; and St. Joseph’s University, Philadelphia, PA 19131

Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B 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 is supported by the Lankenau Hospital Foundation (to L.M.-N. and G.C.P.). N.R. is supported by a research assistantship fellowship from the Brook J. Lenfest Foundation. A.J.M. is the recipient of grants from the Department of Defense Breast Cancer Research Program (BC044350), the Concern Foundation, and the Lance Armstrong Foundation and G.C.P. is the recipient of National Institutes of Health Grants CA109542, CA82222, and CA100123.

² Address correspondence and reprint requests to Dr. Laura Mandik-Nayak, The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096. E-mail address: mandik-nayakl{at}mlhs.org

³ Abbreviations used in this paper: RA, rheumatoid arthritis; ASC, Ab-secreting cell; LN, lymph node; dLN, draining LN; GPI, glucose-6-phosphate isomerase; 1MT, 1-methyl-tryptophan; Treg, T regulatory cell; b.i.d., twice a day.