Immune Dysregulation During Multiple Sclerosis Relapse

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Project Summary/Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that affects over 400,000 people in the US. The most common clinical form of MS presents with a relapsing-remitting clinical course (RRMS). Whereas several immune differences have been shown between RRMS patients and healthy subjects, the immunologic basis of a clinical relapse remains poorly understood. Some studies have shown aberrant immune responses to myelin antigens and defect in regulatory T and B cells during an acute disease relapse. However, the immune dysregulation that underlies the relapse remains unclear. In particular, there is a paucity of longitudinal studies addressing CD4 and CD8 T cell effector and regulatory responses before, during and after an acute relapse. Using innovative approaches, our recent studies have made several interesting observations relating to CD4 and CD8 regulatory T cell biology during acute relapse of MS. We have demonstrated the novel and unexpected immune regulatory function of CNS-specific CD8+ T cells. Interestingly, RRMS patients with quiescent disease and healthy subjects showed comparable levels of CNS-specific CD8 suppressor activity. However, patients during an acute relapse showed a dramatic deficit of CNS-specific suppressor activity, even when CNS-specific CD8 responses could be detected at pre-relapse level. Moreover, as patients attained disease quiescence [with various different therapies], they consistently showed normalization of CNS-specific CD8 suppressor activity. We have further observed that these deficits are correctable by modulation of the cytokine milieu and through understanding of the mechanisms through which immune regulation is achieved. In recent unpublished studies, we have also shown the dysregulation of a novel sub-population of induced CD4+ regulatory T cells during an acute MS relapse. Based on these findings, we hypothesize that an accumulating longitudinal deficit of immune regulatory function and effector resistance results in an MS relapse. As a corollary, we predict that correcting these functional deficits is an important immunologic correlate of disease quiescence. Through the proposed studies, we will address these hypotheses by delineating the longitudinal fluctuation of CD4 and CD8 regulatory ability and its relationship with an MS relapse. We will dissect the various mechanisms of relapse- associated CD8 regulatory deficit and attempt to devise strategies to correct the observed deficits. The proposed studies will provide greater fundamental insights into the immunologic processes underlying disease relapse with the potential for novel immunotherapeutic strategies.