title: RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis.
abstract: BACKGROUND
  We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40.
  
  
  METHODS
  Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.
  
  
  RESULTS
  Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.
  
  
  CONCLUSIONS
  These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.
authors.affiliation: Departments of Surgery, Pathology, Microbiology and Immunology, University of Western Ontario, 1393 Western Road, London, Ontario, N6G 1G9, Canada. xzheng26@uwo.ca
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.forename: Motohiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Xusheng
authors.initials: X
authors.lastname: Zhang
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ichim
authors.forename: Fei
authors.initials: F
authors.lastname: Zhu
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Aminah
authors.initials: A
authors.lastname: Shunnar
authors.forename: Michael H
authors.initials: MH
authors.lastname: Wang
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Robert D
authors.initials: RD
authors.lastname: Inman
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques / Q000379:methods; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D034622:RNA Interference; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D019013:CD40 Antigens; D034741:RNA, Small Interfering; D023201:CD40 Ligand