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

20(OH) 维生素 D3、T 细胞和关节炎

基本信息

批准号：
8697201
负责人：
ANDREW H KANG
金额：
$ 33万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697201
关键词：
Affect Animal Model Arthritis Attenuated Autoimmune Diseases Biochemical CTLA4-Ig Cell Lineage Cells Cholecalciferol Collagen Arthritis Collagen Type II Confocal Microscopy DBA/1 Mouse Development Disease Distal Dose Down-Regulation Effectiveness Enzyme-Linked Immunosorbent Assay Etiology Flow Cytometry Frequencies Genetic Transcription Histology Human Immunization Immunodominant Epitopes Immunosuppressive Agents Inflammatory Inflammatory Response Interferons Interleukin-10 Interleukin-17 Interleukin-4 Intervention Joints Kinetics Ligands Location Lymphoid MAPK14 gene MAPK8 gene Methods Microfluidics Mitogen-Activated Protein Kinases Modality Modeling Molecular Mus Pathogenesis Pathway interactions Pattern Peptides Peripheral Blood Mononuclear Cell Phenotype Production Regulatory T-Lymphocyte Reporter Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Risk Role Severities Signal Pathway Signal Transduction Staining method Stains Supplementation T-Cell Activation T-Lymphocyte Testing Therapeutic Up-Regulation Vitamin D Vitamin D Analog Vitamin D Deficiency Vitamin D3 Receptor Western Blotting Work analog autoimmune arthritis cytokine effective therapy inhibitor/antagonist peptide analog public health relevance research study response success transcription factor treatment strategy

项目摘要

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 non-calcemic 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.

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 可能会降低该疾病的风险或增强治疗该疾病的治疗方法。由 P450scc 启动的新的分泌类固醇生成途径的发现，可产生维生素 D3 羟基衍生物，为 RA 治疗开辟了新的选择。该途径的第一个也是主要产物 20(OH)D3 在浓度高达 30μg/kg 时是无毒的。我们研究了 RA 的分子发病机制，认为 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。例如，由 II 型胶原 (CII) 免疫显性表位的改变肽配体 (APL) 肽（即 A9、CII245-270（A260、B261、N263））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 通过抑制 Th1 和 20(OH)D3 增强对炎症反应的抑制Th17 反应，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将以比单独使用任一疗法更低和更安全的剂量协同下调关节炎的严重程度。然而这种抑制的机制仍然未知。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/调节性细胞因子的分泌，最终导致抑制自身免疫性关节炎；并且非钙血症 20(OH)D3 与经典形式的维生素 D3 [1,25(OH) 2D3] 一样有效且毒性较小。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：目标 1) 检验以下假设：重定向 T 细胞细胞因子谱是 20(OH)D3 增强 APL 减弱 APL 效果的机制。胶原诱导的关节炎，目标 2) 检验以下假设：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，目标 3) 检验假设20(OH)D3 与替代 T 细胞信号通路交叉并影响 APL 驱动的 T 细胞细胞因子的产生。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，以及非钙血症形式的维生素 D 20(OH)D3 是否与 1,25(OH)2D3 一样有效。