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) All Versions of this Article: jimmunol.0901637v1 183/6/3770    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 Oflazoglu, E. Articles by Grewal, I. S. PubMed PubMed Citation Articles by Oflazoglu, E. Articles by Grewal, I. S.

Blocking of CD27-CD70 Pathway by Anti-CD70 Antibody Ameliorates Joint Disease in Murine Collagen-Induced Arthritis

Departments of Preclinical Therapeutics, Seattle Genetics, Bothell, Washington 98021

Rheumatoid arthritis (RA) is characterized by inflammation and cellular proliferation in the synovial lining of joints that result in cartilage and bone destruction. Although the etiology of RA is unclear, activated lymphocytes and proinflammatory molecules, in particular TNF superfamily members, have been implicated in the disease pathology. A TNF superfamily member, CD70, is found on activated lymphocytes and shown to be important in memory and effector responses of lymphocytes. CD70 is expressed at high levels on chronically activated T cells in patients with autoimmune disorders, including RA. The involvement of CD70 in the progression of RA, however, remains unknown. In this study, we report effects of targeting CD70 on disease pathogenesis by using an anti-mouse CD70 Ab in a murine model of collagen-induced arthritis (CIA). In addition to blocking CD70 binding to its receptor CD27, the anti-CD70 Ab used also engages Fc-dependent effector functions including Ab-dependent cellular cytotoxicity, phagocytosis, and complement fixation. Treatment of mice with anti-CD70 Ab both before the onset or after the established disease in CIA model resulted in marked improvements in disease severity and significant reduction in the production of autoantibodies. Histopathological analyses of the joints of mice revealed a substantial reduction of inflammation, and bone and cartilage destruction in response to the anti-CD70 Ab treatment. These results uncover a novel role for CD27-CD70 interactions in the regulation of in vivo inflammatory response leading to arthritis, and provide a molecular basis to support the rationale for anti-CD70 therapy for autoimmune and inflammatory diseases.

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 E.O. and T.E.B. contributed equally to this work.

² Current address: Department of Oncology Discovery, Wyeth Pharmaceuticals, 401 N. Middletown Road, Pearl River, NY 10965.

³ Address correspondence and reprint requests to Dr. Iqbal S. Grewal, Department of Preclinical Therapeutics, Seattle Genetics, Inc. 21823 30th Drive SE, Bothell, WA 98021. E-mail address: igrewal{at}seagen.com

⁴ Abbreviations used in this paper: DC, dendritic cell; sCD27, soluble form of CD27; RA, rheumatoid arthritis; SLE, systemic lupus erythematosis; CIA, collagen-induced arthritis; CDC, complement-dependent cytotoxicity; ADCP, Ab-dependent cellular phagocytosis; ADCC, Ab-dependent cellular cytotoxicity; CII, type II collagen.