Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

Objective. The complement system is important in the development of autoimm une inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of c omplement activity. Studies on models of autoimmunity have demonstrated tha t soluble CR1 (sCR1) is a potent therapeutic agent. The present study was t hus undertaken to investigate the feasibility of antiinflammatory gene ther apy to prevent CIA by delivery of genes encoding truncated sCR1 (tsCR1) and dimeric tsCR1-Ig. Methods. Syngeneic fibroblasts or arthritogenic splenocytes, engineered to express tsCR1 using retrovirus-mediated gene transfer, were injected into D BA/1 recipients that had been immunized with bovine type II collagen (CII), In separate experiments, naked DNA containing tsCR1 and tsCR1-Ig genes was injected intramuscularly into the immunized animals. The clinical developm ent of arthritis was monitored, anti-CII levels measured, and antigenic T c ell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibi tory effect on the alternative complement pathway in mouse serum. Results. Treatment of CII-immunized mice with the tsCR1-expressing cells in hibited development of CIA, reduced anti-CII antibody levels, and inhibited T cell response to CII in vitro. Intramuscular injections of DNA encoding the CR1 genes prevented the progression of disease. Furthermore, compared w ith full-length sCR1, purified tsCR1-Ig was more active in inhibiting the m urine alternative complement pathway. Conclusion. Our findings demonstrated that tsCR1 and tsCR1-Ig, when deliver ed via gene therapy, had a beneficial effect on autoimmune inflammation. Th ese results indicate that targeting the complement system in RA patients ma y be of clinical importance.