Immunotherapy in neuromuscular disorders: current and future strategies

Autoimmune mechanisms have recently been implicated in the pathogenesis of an increasing number of neuromuscular diseases. Many of these diseases can be treated with immunotherapeutic agents that are currently available--often with striking success. However, lack of specificity and adverse side effects impose limits on the effectiveness of these immunosuppressive treatments. This article reviews the basic principles of autoimmunity and immune tolerance, and outlines strategies that produce (a) generalized immunosuppression; (b) "selective" immunotherapy; and (c) "antigen-specific" immunotherapy. General immunosuppressive treatments, which are the ones most commonly used in current practice, down-regulate the immune system at multiple levels in "shotgun" fashion. The agents described here include: adrenal corticosteroids, azathioprine, cyclophosphamide, chlorambucil, methotrexate, total lymphoid irradiation, plasmapheresis, and intravenous immunoglobulin. "Selective" immunotherapeutic strategies are designed to interfere with mechanisms intrinsic to the immune system. Agents that are now being used clinically, or are in advanced stages of development include: cyclosporin A, which interferes with synthesis of the cytokine interleukin 2 (IL2); IL2 toxin, which binds to IL2 receptors on activated T cells, is endocytosed, and kills the cells; and CTLA4Ig, which blocks costimulatory molecules, thus preventing full activation of T cells. We have found that combinations of the selective agents may enhance their effectiveness. "Specific" strategies are designed to inactivate or suppress antigen-specific T cells. Oral administration of autoantigens has been shown to prevent experimental autoimmune diseases specifically, but the conditions required to suppress ongoing autoimmune diseases are capricious, and depend on many factors. Finally, we describe a method that is still in the experimental stage, which is designed to modify the individual's own antigen-presenting cells so that they will target and inactivate antigen-specific T cells, and thereby turn off the specific autoimmune response. Currently available immunosuppressive methods can now be used successfully to treat many autoimmune neuromuscular diseases, and the application of selective and specific immunotherapeutic strategies promises more precise and effective treatment in the future.