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Selective Targeting of B Cells with Agonistic Anti-CD40 Is an Efficacious Strategy for the Generation of Induced Regulatory T2-Like B Cells and for the Suppression of Lupus in MRL/lpr Mice¹

Paul A. Blair^2,*, Karina A. Chavez-Rueda^2,*,, Jamie G. Evans^*, Mark J. Shlomchik, Ayad Eddaoudi, David A. Isenberg^*, Michael R. Ehrenstein^* and Claudia Mauri^3,*

^* Centre for Rheumatology Research, Department of Medicine, University College London, London, United Kingdom; Unidad de Investigación Médica en Immunologia, Hospital de Pediatria, Mexico City, Mexico; Department of Laboratory Medicine and Immunology, Yale University School of Medicine, New Haven, CT 06510; and Molecular Immunology Unit, Institute of Child Health, London, United Kingdom

We have previously reported that IL-10⁺ regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10⁺CD4⁺T cells, and conveyed a regulatory effect to CD4⁺T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus.

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 Wellcome Trust (Grant 068629 to C.M.), the University College of London Hospital charities Clinical Research Development Committee (Grant G140 to C.M.) and equipment Arthritis Research Campaign Grant ID 17746. P.A.B. is supported by the Oliver Bird Rheumatism Programme (Grant RHE/001124/G to D.A.I.). K.A.C.R. is supported by the Instituto Mexicano Del Seguro Social. M.J.S. was supported by National Institutes of Health Grant R01AR044077.

² P.A.B. and K.A.C.-R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Claudia Mauri, Centre for Rheumatology Research, Department of Medicine, University College of London, 46 Cleveland Street, London W1T4 JF, U.K. E-mail address: c.mauri{at}ucl.ac.uk

⁴ Abbreviations used in this paper: Breg, regulatory B cell; CIA, collagen-induced arthritis; Treg, regulatory T cell; hCD20, human CD20; AP, alkaline phosphatase; DAPI, 4',6-diamidino-2-phenylindole dihydrochloride; MZ, marginal zone; FO, follicular; LN, lymph node.

⁵ The online version of this article contains supplemental material.