Protection against autoimmune arthritis induced by hsp65-mediated tolerance involves enhanced production of both IFN-γ and antigen-specific antibodies (128.23)

Abstract

Abstract Induction of antigen-specific immune tolerance is a desired goal of many therapeutic approaches against autoimmune diseases. Adjuvant arthritis (AA), an animal model of human rheumatoid arthritis (RA), is a Th1-mediated disease and it can be induced in Lewis (LEW) (RT.1l) rats by s.c. injection of heat-killed M. tuberculosis. Arthritic LEW rats raise T cell and antibody responses to mycobacterial heat shock protein 65 (Bhsp65). We employed a novel tolerogenic approach by introducing a Bhsp65-IgG heavy chain gene construct retrovirally ex vivo into B cells and then injecting these cells i.p. into syngeneic recipients. In another approach, we injected LEW rats i.p. with soluble Bhsp65. The former approach was successful in preventing as well as treating ongoing AA, whereas the latter was effective in the prevention. We observed significantly reduced T cell proliferative response to Bhsp65 in rats injected with either Bhsp65-IgG-expressing B cells or soluble Bhsp65 compared to the respective controls. This reduced T cell proliferation was restored by IL-2. Interestingly, there was increased production of IFN-γ by Bhsp65-primed cells in the Bhsp65-treated LEW rats, whereas not much change was observed in IL-10 secretion. The frequency of CD4+FoxP3+ T cells in peripheral blood did not change following tolerization. However, a high level of serum anti-Bhsp65 antibodies was observed in tolerized rats much earlier during the course of AA than that in controls. Regulation of a Th1-mediated autoimmune disease by a pro-inflammatory cytokine (IFN-γ) and the disease-protective attribute of antibodies represent novel aspects of this study. B cell-mediated suppression of established autoimmunity offers a promising approach for the treatment of RA. (Support: Arthritis Foundation and NIH)