A variety of experimental approaches are currently being evaluated for controlling CD4 T helper 1 (Th 1)-mediated autoimmune pathology. Here, Stephen Miller and William Karpus compare and contrast the efficacies of various antigen-specific regulatoo, strategies. Particular emphasis is placed on the mechanisms of peripheral immune tolerance and bow this may be used in tbe treatment and analysis of the pathologic T-cell repertoire in ataoimmune and virus-reduced demyelinating diseases.

An understanding of the pathogenesis of T-cell-mediated autoimmur. e diseases has derived mainly from the study of experimental animal models. For example, potential immunopathological mechanisms of multiple sclerosis (MS) in humans have been predicted from the study of murine models of T-cell-mediated central nervous system! CNS) demyelination. MS is a neurological disease of major, ocio-economic importance, has a possible viral trigger, and presents clinically as either a chronic-pro-~ essive or a relapsing-remitting paralytic course I. However, despite many years of study, it is still not clear whether the pathology in MS is due to neuroantigenspecific CD4* T-cell-mediated autoimmune response (s) and/or to bystander myelin damage resulting from an inflammatory response triggered by T cells targeting a CNS-persisting virus. Autoimmune responses could result directly from a'natural'loss of self tolerance or from sensitization to neuroantigen secondary to a viral infection. For instance, sensitization could occur following release of sequestered neuroantigens/neuroepitopes or by triggering self-reactive T cells via molecular mimicry. However, in terms of the autoimmune effector nature of MS, either as a primary effector mechanism or secondary to a virus infection, there is no convincing evidence that MS patients display significantly elevated humoral or T-cell-mediated responses to the major myelin proteins] myelin basic protein (MBP) and proteolipid protein (PLP)] when compared with appropriate controls-'. Similarl); the search for an MS-triggering virus has proved unproductiv0.