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

• Published in: The Journal of immunology (1950) Vol. 183; no. 6; pp. 3770 - 3777
• Main Authors: Oflazoglu, Ezogelin, Boursalian, Tamar E, Zeng, Weiping, Edwards, Ana C, Duniho, Steve, McEarchern, Julie A, Law, Che-Leung, Gerber, Hans-Peter, Grewal, Iqbal S
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.09.2009
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Arthritis, Experimental - drug therapy; Arthritis, Experimental - pathology; Autoantibodies - analysis; Bone and Bones - drug effects; Bone and Bones - pathology; Cartilage - drug effects; Cartilage - pathology; CD27 Ligand - antagonists & inhibitors; Disease Progression; Inflammation - prevention & control; Joint Diseases; Male; Mice; Tumor Necrosis Factor Receptor Superfamily, Member 7 - antagonists & inhibitors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901637

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.