Abstract

The defining characteristic of an autoimmune disease is the existence of T- and B-cell autoreactivity directed against self proteins (autoantigens). The early events that precipitate autoreactivity in human autoimmune disease remain obscure. Once established, the autoreactive process itself may or may not be directly relevant to the pathological events involved in the disease. In patients with established rheumatoid arthritis, for example, on-going joint damage is most likely the result of a self-perpetuating inflammatory process that has few features of tissue-specific autoreactivity. In type 1 diabetes mellitus (DM), on the other hand, autoreactivity directed against the target cell in the pancreas reaches its peak of intensity around the time of clinical diagnosis and typically wanes only after the target cell has been destroyed. These are examples at opposite ends of a continuum but most theoretical models used to explain autoimmune disease invoke a period of autoreactivity against a specified protein autoantigen(s) as a critical phase in disease development. Work in animal models indicates that this phase may be susceptible to regulation by administration of the inciting autoantigen. In this review several key questions will be addressed in relation to antigen-specific immunotherapy (ASI) for autoimmune disease. First, does it work in animal models, and by what mechanism(s) of action? How should we best harness these effects for human disease? How will we know when it has worked? And finally, will it work in established disease or will prophylaxis be required? In terms of autoantigen administration, we will focus mainly upon systemic rather than mucosal routes, which have been discussed extensively in other recent reviews.1,2 A particular emphasis will be placed upon the issues to be faced in transposing ASI as a therapeutic option from animal into clinical studies.

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