title: Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis.
abstract: OBJECTIVE
  The complement system is important in the development of autoimmune inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of complement activity. Studies on models of autoimmunity have demonstrated that soluble CR1 (sCR1) is a potent therapeutic agent. The present study was thus undertaken to investigate the feasibility of antiinflammatory gene therapy 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 DBA/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 development of arthritis was monitored, anti-CII levels measured, and antigenic T cell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibitory effect on the alternative complement pathway in mouse serum.
  
  
  RESULTS
  Treatment of CII-immunized mice with the tsCR1-expressing cells inhibited 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 with full-length sCR1, purified tsCR1-Ig was more active in inhibiting the murine alternative complement pathway.
  
  
  CONCLUSIONS
  Our findings demonstrated that tsCR1 and tsCR1-Ig, when delivered via gene therapy, had a beneficial effect on autoimmune inflammation. These results indicate that targeting the complement system in RA patients may be of clinical importance.
authors.affiliation: Kennedy Institute of Rheumatology, Hammersmith, and St. Bartholomew's and Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, UK.
authors.forename: H
authors.initials: H
authors.lastname: Dreja
authors.forename: A
authors.initials: A
authors.lastname: Annenkov
authors.forename: Y
authors.initials: Y
authors.lastname: Chernajovsky
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000628:therapy*; D001327:Autoimmune Diseases / Q000188:drug therapy; D003094:Collagen; D003170:Complement Pathway, Alternative / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage; D018450:Disease Progression; D005347:Fibroblasts / Q000821:virology*; D015316:Genetic Therapy / Q000379:methods*; D007267:Injections; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D011951:Receptors, Complement / Q000235:genetics / Q000627:therapeutic use*; D012192:Retroviridae Infections / Q000503:physiopathology*
chemical_list: D011951:Receptors, Complement; D003094:Collagen; D004247:DNA