RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis.
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.
Zheng
Xiufen
X
Departments of Surgery, Pathology, Microbiology and Immunology, University of Western Ontario, 1393 Western Road, London, Ontario, N6G 1G9, Canada. xzheng26@uwo.ca
Suzuki
Motohiko
M
Zhang
Xusheng
X
Ichim
Thomas E
TE
Zhu
Fei
F
Ling
Hong
H
Shunnar
Aminah
A
Wang
Michael H
MH
Garcia
Bertha
B
Inman
Robert D
RD
Min
Wei-Ping
WP
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
D019013:CD40 Antigens; D034741:RNA, Small Interfering; D023201:CD40 Ligand