RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis
- Equal contributors
1 Departments of Surgery, Pathology, Microbiology and Immunology, University of Western Ontario, 1393 Western Road, London, Ontario, N6G 1G9, Canada
2 Division of Rheumatology, Department of Medicine, Toronto Western Hospital, University Health Network, 1E423 - 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada
3 Medistem Inc, 9255 Towne Centre Drive, San Diego, CA 92121-3038, USA
4 Multi-Organ Transplant Program, London Health Sciences Centre, 339 Windermere Road, London, Ontario, N6A, 5A5, Canada
5 Transplantation and Regenerative Medicine, Lawson Health Research Institute, 339 Windermere Road, London, Ontario, N6A, 5A5, Canada
Arthritis Research & Therapy 2010, 12:R13 doi:10.1186/ar2914Published: 26 January 2010
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.
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.
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.
These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.