20(OH) Vit D3, T Cells, and Arthritis

描述(申请人提供)：引用维生素D缺乏与类风湿性关节炎(RA)相关的研究表明，维生素D补充剂可能会降低这种疾病的风险或加强治疗方法。P450scc启动的产生维生素D3羟基衍生物的新的激素合成途径的发现，为RA的治疗开辟了新的选择。该途径的第一个也是主要的产物20(OH)D3在浓度高达30g/kg时是无毒的。本文认为RA是一种以T细胞调节失调为特征的自身免疫性疾病，使用维生素D类似物可增强T细胞的免疫调节作用，探讨了RA的分子发病机制。例如，由II型胶原(CII)的免疫优势表位A9、CII245-270(A260、B261、N263)的多肽配体(APL)肽激活的T细胞上调维生素D受体(VDR)的表达，因此1，25(OH)2D3和20(OH)D3都通过抑制Th1和Th17的反应而增强对炎症反应的抑制，同时增加Th2细胞因子和IL-10的产生。我们认为，类似肽和维生素D联合治疗的最终结果将是在更低和更安全的剂量下协同下调关节炎的严重程度。然而，这种压制的机制仍不清楚。我们的中心假设是，APL诱导的T抑制细胞上调维生素D受体(VDR)，允许维生素D3直接作用于T细胞，增强对炎性细胞因子的抑制和Th2/调节性细胞因子的分泌，最终导致抑制自身免疫性关节炎；非钙血症性20(OH)D3将与经典形式的维生素D3[1，25(OH)2D3]一样有效，毒性更低。为了了解维生素D增强这种反应的机制，我们提出了以下特定目的：目的1)检验20(OH)D3通过改变T细胞细胞因子谱是20(OH)D3增强APL在减轻胶原诱导的关节炎中的有效性的机制的假说，目的2)检验通过结合两种干预措施[20(OH)D3和APL]可以增强自身免疫性关节炎的调节的假说，以及目的3)检验20(OH)D3交叉替代T细胞信号通路并影响APL驱动的T细胞细胞因子产生的假说。这些实验的成功完成将证明维生素D和类似肽是否协同作用来抑制自身免疫性关节炎，以及非钙化形式的维生素D，20(OH)D3是否与1，25(OH)2D3一样有效。

DESCRIPTION (provided by applicant): Studies citing vitamin D deficiency associated with rheumatoid arthritis (RA) have indicated that vitamin D supplementation might reduce the risk of or enhance therapeutic approaches to treat this disease. The discovery of a new secosteroidogenic pathway initiated by P450scc that produces vitamin D3 hydroxyderivatives has opened new options in treatment for RA. This first and main product of the pathway, 20(OH)D3, is non-toxic at concentrations as high as 30?g/kg. We have approached the molecular pathogenesis of RA under the thesis that RA is an autoimmune disorder characterized by T cell dysregulation and that the use of vitamin D analogs can enhance the immunomodulatory effects of T cells. For example, T cells activated by altered peptide ligand (APL) peptide of the immunodominant epitope of type II collagen (CII), ie A9, CII245-270 (A260, B261, N263), upregulate the expression of the vitamin D receptor (VDR) so that both 1,25(OH)2D3 and 20(OH)D3 enhance the suppression of the inflammatory responses by inhibiting Th1 and Th17 responses while increasing the production of Th2 cytokines and IL- 10. We feel that the net result of combining therapies with both analog peptides and vitamin D will be a synergistic downregulation of the severity of arthritis at lower and safer doses than either therapy alone. Yet the mechanism of this suppression remains unknown. Our central hypothesis is that T inhibitory cells induced by the APL upregulate the Vitamin D receptor (VDR) allowing vitamin D3 to act directly on T cells to enhance both the suppression of inflammatory cytokines and the secretion of Th2/regulatory cytokines ultimately leading to suppression of autoimmune arthritis; and that the noncalcemic 20(OH)D3, will be as effective and less toxic than the classical form of vitamin D3 [1,25(OH) 2D3]. To understand the mechanism by which vitamin D enhances this response we propose the following specific aims: Aim 1) To test the hypothesis that redirecting the T cell cytokine profile is a mechanism by which 20(OH)D3 enhances the effectiveness of an APL in attenuating collagen-induced arthritis, Aim 2) To test the hypothesis that modulation of autoimmune arthritis can be enhanced by combining two interventions[ 20(OH)D3 and an APL], and Aim 3) To test the hypothesis that 20(OH)D3 intersects the alternate T cell signaling pathway and affects APL driven T cell cytokine production. Successful completion of these experiments will demonstrate if vitamin D and analog peptides work in synergy to suppress autoimmune arthritis and whether the noncalcemic form of vitamin D, 20(OH)D3 is as effective as 1,25(OH)2D3.