Predicting anti-arthritic drug effects in collagen-induced arthritis using short-term mechanistic models of collagen II immunity

Abstract

Novel anti-arthritic drugs are often assessed in murine collagen-induced arthritis (CIA), which is a widely used pre-clinical model of rheumatoid arthritis. However, CIA studies are lengthy, development of arthritis is not synchronised and not all animals develop disease. Work conducted in this thesis addressed some of these issues by developing short-term mechanistic models of collagen II (CII) immunity. Drug effects on CII-induced hypersensitivity, anti-CII antibodies and ex vivo CII stimulated CD4+ T cell proliferation in mice 14 days post-CII sensitisation were assessed and compared to their anti-arthritic effect in CIA. As this thesis progressed, it was reported that IL-17 secreting CD4+ T helper (Th17) cells represent a population of cells distinct from interferon gamma (IFNγ) secreting Th1 and IL-4 secreting Th2 cells and may be involved in autoimmune disease. However, the role of IL-17 and Th17 cells in CIA and CII immunity was not defined. The role of IL-17 and its relationship with Th1 and Th2 cells was investigated in the CII stimulated CD4+ T cell assay. Results showed that CII specific Th1 and Th17, but not Th2 cells, are present in cultures of cells from CII sensitised mice. Addition of anti-IL-17 to these cultures increased the number of CII specific IFNγ secreting CD4+ T cells. Literature evidence suggests that IFNγ is protective in CIA. This increase in IFNγ may therefore represent a novel mechanism of action by which anti-IL-17 exerts some of its anti-arthritic activity. This thesis has shown that short-term models of CII immunity can predict anti-arthritic drug effects in CIA. A novel screening cascade has been proposed which could be used in drug discovery and may reduce the number of animals required for CIA studies. Moreover, the differential effect of anti-arthritic drugs in these models suggests they can discriminate between drugs and identify novel mechanisms of action.