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

Abstract

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.

CD27 costimulation is not critical for the development of asthma and respiratory tolerance in a murine model

“…Treatment of mice with anti-CD70 mAb prevented the development of Th1-mediated experimental autoimmune encephalomyelitis (EAE) due to the inhibition of TNF-␣ production. Recently published data of Oflazoglu underlines the therapeutic potentiality of anti-CD70 treatment in autoimmune diseases [44]. CD70 inhibition resulted in reduced production of autoantibody, decrease of inflammation and bone and cartilage destruction, leading to marked improvement of clinical symptoms in a murine model for rheumatoid arthritis.…”

Osteoclast precursors in murine bone marrow express CD27 and are impeded in osteoclast development by CD70 on activated immune cells

“…It will be of interest to find examples of this mechanism in immune-related disease models. In murine collagen-induced arthritis, CD70-blocking antibody attenuated disease, reducing immune cell infiltration of the joints, anti-collagen antibody levels, and bone erosion (38). Thus, the CD27/ CD70 pathway promotes rather than inhibits the detrimental effects in arthritis, in line with its driving force in chronic immune activation (18,23,24).…”

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases

“…Genetic deletion or neutralization of either CD27 or CD70 in mice has revealed a pathogenic role for the CD27–CD70 axis in many inflammatory settings 4–6,107 . For example, in mice with collagen-induced arthritis, blocking CD27–CD70 interactions with anti-CD70 antibody reduces bone and cartilage erosion and inflammatory infiltrates in the joints, and decreases collagen-specific antibody production, even when the treatment is initiated after disease onset 108 . In the synovial fluid of patients with RA, soluble CD27 levels and CD27 + T cell numbers are elevated and correlates with the levels of rheumatoid factor, supporting a role for CD27 in human RA 109 .…”