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

描述（由申请人提供）：引用与类风湿性关节炎（RA）相关的维生素D缺乏的研究表明，补充维生素D可能会降低这种疾病的风险或增强治疗方法。由P450scc启动的一种产生维生素D3羟基衍生物的新的类固醇生成途径的发现为治疗RA开辟了新的选择。该途径的第一个也是主要产物20(OH)D3在浓度高达30g /kg时是无毒的。我们在RA是一种以T细胞失调为特征的自身免疫性疾病，使用维生素D类似物可以增强T细胞的免疫调节作用的基础上探讨了RA的分子发病机制。例如，被II型胶原（CII）免疫优势表位的改变肽配体（APL）肽激活的T细胞，即A9， CII245-270 (A260, B261, N263)，上调维生素D受体（VDR）的表达，使得1,25(OH)2D3和20(OH)D3通过抑制Th1和Th17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，将类似肽和维生素D联合治疗的最终结果是，与单独使用任何一种治疗相比，以更低、更安全的剂量协同降低关节炎的严重程度。然而，这种抑制的机制尚不清楚。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），使维生素D3直接作用于T细胞，增强对炎症细胞因子的抑制和Th2/调节细胞因子的分泌，最终导致自身免疫性关节炎的抑制；而不含钙的20(OH)D3与传统形式的维生素D3 [1,25(OH) 2D3]一样有效，而且毒性更小。为了了解维生素D增强这种反应的机制，我们提出以下具体目标：目的1)验证重定向T细胞细胞因子谱是20（OH)D3增强APL减轻胶原诱导关节炎有效性的机制的假设；目的2)验证联合两种干预措施[20(OH)D3和APL]可以增强自身免疫性关节炎的调节的假设；目的3）验证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设。这些实验的成功完成将证明维生素D和类似肽是否协同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125 (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.