title: Binding immunoglobulin protein resolves rheumatoid synovitis: a xenogeneic study using rheumatoid arthritis synovial membrane transplants in SCID mice.
abstract: BACKGROUND
  Binding immunoglobulin protein (BiP) has previously shown powerful anti-inflammatory properties in the collagen-induced arthritis (CIA) model, where a single dose of BiP has proved to be both a long-term prophylactic and therapeutic. In both CIA and human in vitro studies, BiP induced regulatory T cells. The present investigation looked at the anti-inflammatory effect of BiP on inflamed human synovial tissue transplanted into severe combined immunodeficient mice (SCID), a chimaeric in vivo model previously used to test the efficacy of biologic therapies.
  
  
  METHODS
  Rheumatoid arthritis synovial membrane (RASM) was engrafted into SCID mice. Following successful engraftment, mice were intravenously injected with BiP or human serum albumin in the presence or absence of anti-IL-10 mAb. Twelve days later the grafts were removed for analysis and human cytokines in the sera were quantified by ELISA. The extent of residual inflammatory cellular infiltrate in the synovial explants was determined by weight of the explants.
  
  
  RESULTS
  The RASM transplants from mice treated with BiP showed visual reduction in cellular infiltrate and downregulation of all quantifiable features of inflammation as assessed by the Koizumi or Rooney histological criteria. Also downregulated were HLA-DR, CD86, IL-6 and TNFα expression as assessed by immunohistology. ELISA detected significantly less human IL-6 circulating in the BiP-treated mouse serum. After removal of transplanted tissue 12 days post administration of BiP, the RASM explants from the BiP-treated SCID mice weighed significantly less, indicating a suppression of tissue inflammation. Mice given concomitant neutralising anti-IL-10 antibody and BiP showed no such suppression.
  
  
  CONCLUSIONS
  BiP has anti-inflammatory properties partially dependent on the downregulation of HLA-DR and co-stimulatory molecules and the predominant production of IL-10.
authors.affiliation: Biomedical Engineering Center, Toin University of Yokohama, 1614 Kurogane-cho, Aoba-ku, Yokohama 225-8502, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Ochiai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuno
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Panayi
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Corrigall
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006360:Heat-Shock Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D013583:Synovial Membrane / Q000637:transplantation*; D014183:Transplantation, Heterologous; D019737:Transplants
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins