ABSTRACT The treatment of autoimmune diseases by gene therapy methods is promising but still in its infancy. Gene therapy allows relatively constant delivery of many cytokines or cytokine inhibitors at therapeutic levels. It provides a convenient, effective and relatively inexpensive way of administering these molecules, obviating several limitations of protein administration. Viral and nonviral vectors have been used to protect against autoimmune diseases in several models. TGF-β1 gene therapy protects against autoimmune diabetes, experimental allergic encephalomyelitis (EAE), arthritis, colitis and murine lupus. IL-4 and IL-10 have also proved effective in several autoimmune conditions. The delivery of inhibitory soluble cytokine receptors, or other cytokine inhibitors, by these methods is also effective. IL-1 receptor antagonist (IL-IRa), soluble interferon γ (IFNγ) receptor (IFNγR)/IgG-Fc fusion proteins or soluble tumour necrosis factor α (TNFα) receptors protect from autoimmune and/or inflammatory conditions. These inhibitors, unlike many cytokines, have little or no toxic potential. In our laboratory, we have relied on injection of naked plasmid DNA into skeletal muscle. These plasmid vectors are nonimmunogenic, can be repeatedly administered and are expressed in muscle for periods ranging from weeks to months. Moreover, soluble receptors are constructed from nonimmunogenic self elements unlikely to be neutralized by the host immune response, allowing long-term therapy of chronic inflammatory diseases.
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