IMMUNOREGULATORY EFFECTS OFVITAMIN D AND ITS MECHANISM OF ACTION IN CD4+ T CELLS

摘要

Vitamin D (VitD) deficiency has been implicated in the pathogenesis of multiple diseases including chronic kidney disease (CKD). VitD has direct effects on most cells in the innate and adaptive immune system including; CD4+ T cells and dendritic cells (DCs) both of which express the vitamin D receptor (VDR). This thesis, divided into two distinct parts, dissects the effects of: a) in vivo repletion of VitD in a placebo controlled, double blinded clinical trial in CKD patients. Here we hypothesised that repletion with cholecalciferol in VitD insufficient/deficient adult patients would ameliorate systemic inflammation. And the effects of b) VitD treatment of CD4+ T cells in vitro using multiple techniques to delineate the mechanisms influencing cytokine regulation. Here we hypothesised that VitD treatment of CD4+ T cells would, through binding of liganded VDR, lead to epigenetic modifications affecting genes involved in the regulation of cytokine production. In vivo we show that VitD repletion in VitD-deficient and insufficient patients with early stage CKD has immunoregulatory effects on circulating myeloid DCs by reducing expression of HLA-DR (a marker of mature DC phenotype). In vitro we identify a novel signaling pathway in CD4+ T cells, induced by VitD. The hallmark effect of VitD on CD4+ T cells was the induction of an immunoregulatory phenotype characterized by inhibited Th1 and Th17 cytokines and induction of the antiinflammatory cytokine IL-10, a process we show to be regulated by induction of IL-6 and subsequent STAT3 signalling. We further show that these processes are genetically regulated by histone modifications driven by liganded VDR, both at putative enhancer and promoter sites. These findings, most notably, have implications for dysregulated immunoregulation in the setting of inflammatory skin diseases and the development of novel therapeutics for the treatment of these conditions.