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B7RP-1 Blockade Ameliorates Autoimmunity through Regulation of Follicular Helper T Cells

Yi-Ling Hu^*, Daniela P. Metz^*, James Chung, Gerald Siu¹ and Ming Zhang^2,*

^* Department of Inflammation and Department of Medical Sciences, Amgen, Inc., Thousand Oaks, CA 91320

Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T_FH cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T_FH cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F₁ mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T_FH cells and GC B cells as well as an overall decrease in the frequency of ICOS⁺ T cells. Coculture experiments of Ag-primed B cells with CXCR5⁺ or CXCR5^– T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T_FH cell pool is an important mechanism by which ICOS regulates Ab production.

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 Current address: Immunoinflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY U.K.

² Address correspondence and reprint requests to Dr. M. Zhang, Amgen Inc., M/S B29-2-C, Amgen Centre Drive, Thousand Oaks, CA 91320. E-mail address: mingz{at}amgen.com

³ Abbreviations used in this paper: GC, germinal center; T_FH cell, follicular T helper cell; CIA, collagen-induced arthritis; CII, collagen II; NZB/NZW, New Zealand Black/New Zealand White; PNA, peanut agglutinin; SLE, systemic lupus erythematosus.