Multiple sclerosis (MS) is a common inflammatory disorder of the CNS characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Interferon beta (IFN?) has been shown to decrease clinical relapses, reduce brain MRI activity, and slow progression of disability. However, the effect of this treatment is partial, and a significant amount of patients are not responders. The overall goal of this proposal is to characterize the mechanisms involved in the response to IFN? therapy in MS. A Clinical Core has established and maintains a dataset of patients with relapsing remitting MS treated with IFN?. The Core has sequentially collected blood from study participants and store genomic DNA, total RNA, peripheral blood lymphocytes (PBMC) and sera for the studies proposed in this application. Stringent and well established primary and secondary clinical endpoints are available to investigate promising relationships between candidate immunological (specific aim 1, subcontract B), molecular (specific aim 2) and genetic (specific aim 3) surrogate markers and the clinical response to treatment. ? ? Based on the hypothesis that IFN? is a pleiotropic immunoregulatory reagent, a multi-analytical longitudinal strategy was designed to elucidate basic therapeutic mechanisms and identify the patients who will benefit the most from this mode of therapy.
Specific Aim 1 is primarily concerned with the expression of cellular markers of activation following treatment.
In Specific Aim 2, kinetic (real time)-PCR will be used to analyze transcriptional profiles in PBMC of IFN? treated patients. Finally, Specific Aim 3 is a pharmacogenomic study of potential gene-immunotherapy interactions. ? ? A comprehensive multi-analytical strategy was designed and is presented in this proposal to generate reliable working models for the understanding of the physiological mechanisms of IFN? administration in autoimmune demyelination. In addition to new insights into the fundamental biology of interferons, our results will potentially identify surrogate markers of activity, and define the molecular basis of interferon response heterogeneity.
