Fumarates suppress Th1 responses by blocking IL-12 and IL-23 production by dendritic cells via distinct pathways.

IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-γ-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.

Summary The adaptive immune system is thought to be a rich source of protein biomarkers, but diagnostically useful antibodies remain unknown for a large number of diseases. This is, in part, because the antigens that trigger an immune response in many diseases remain unknown. We present here a general and unbiased approach to the identification of diagnostically useful antibodies that avoids the requirement for antigen identification. This method involves the comparative screening of combinatorial libraries of unnatural, synthetic molecules against serum samples obtained from cases and controls. Molecules that retain far more IgG antibodies from the case samples than the controls are identified and subsequently tested as capture agents for diagnostically useful antibodies. The utility of this method is demonstrated using a mouse model for multiple sclerosis and via the identification of two candidate IgG biomarkers for Alzheimer's Disease.

Objective: To study the safety profile and characterize the immunologic effects of high-vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS).Methods: In this double-blind, single-center randomized pilot study, 40 patients with relapsingremitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months.Results: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the lowdose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17T cells (p 5 0.03), and effector memory CD4 1 T cells (p 5 0.021) with a concomitant increase in the proportion of central memory CD41 T cells (p 5 0.018) and naive CD4 1 T cells (p 5 0.04). These effects were not observed in the low-dose group.Conclusions: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD41 T cells and decreased proportion of effector memory CD41 T cells with concomitant increase in central memory CD4 1 T cells and naive CD4 1 T cells. Classification of evidence:This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects. 6,7 These observations may reflect the pleiotropic immunomodulatory effects of vitamin D, involving the innate and adaptive immune system. 7-9The majority of studies examining the immunologic effects of vitamin D have been conducted either in vitro or in animal models, and human studies have employed differing methods and produced discrepant results. [10][11][12] The immunologic effects of high-dose compared to lowdose vitamin D in patients with MS remain unclear. We also sought to confirm that cholecalciferol at 10,000 IU daily is well-tolerated in patients with MS.