Systemic gene therapy for arthritis.
Based on the beneficial effects of antibodies to tumor necrosis factor (TNF)-alpha and inhibitory cytokines, gene delivery of cytokines and cytokine inhibitors has been tried and shown to be of therapeutic benefit in the collagen-induced arthritis model in DBA/1 mice. The clinical beneficial effects are accompanied by an effect at the level of immune functions. We have tested the cytokines transforming growth factor (TGF)-beta 1 and interferon (IFN)-beta, a small molecular weight dimeric p75 TNF receptor, as well as a p55 TNF receptor on an immunoglobulin (Ig) backbone. Inhibition of the complement system using a soluble form of complement receptor 1 also has been shown to block B- and T-cell functions. These molecules were expressed in vivo from syngeneic arthritogenic lymphocytes or immortalized fibroblasts. Because in human disease the antigen driving the autoimmune arthritic response is not defined, we have engaged in the targeting of T-cells to collagen type II, by engineering chimeric antibody-type recognition fused to cytoplasmic signaling domains of cellular receptors. From this spectrum of gene therapy approaches, effective in the mouse, it is hoped that some will be able to be transferred to humans.
Chernajovsky
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Molecular Biology Laboratory, Kennedy Institute of Rheumatology, London, UK.