Vitamin D and the Immune System

维生素 D 和免疫系统

• 批准号: 8111567
• 负责人: SYLVIA S CHRISTAKOS
• 金额: $ 25.3万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111567
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Area; Autoimmune Diseases; Binding Sites; Biomedical Research; Brain; CD4 Positive T Lymphocytes; Cells; Clinical Research; DNA; Disease; Dose; Endocrine system; Experimental Autoimmune Encephalomyelitis; Exploratory/Developmental Grant; Gene Targeting; Genes; Genetic Transcription; Helper-Inducer T-Lymphocyte; IL6 gene; Immune; Immune response; Immune system; Immunology; Inflammation; Inflammatory; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-6; Lead; Mediating; Modeling; Multiple Sclerosis; Mus; Paralysed; Patients; Production; Regulatory T-Lymphocyte; Repression; Risk; Role; Spinal Cord; Splenocyte; T-Lymphocyte Subsets; Therapeutic; Time; Transforming Growth Factor beta; Vitamin D; Vitamin D3 Receptor; bone loss; cytokine; genome-wide analysis; immune function; in vivo; interleukin-22; interleukin-23; lymph nodes; new therapeutic target; orphan nuclear receptor ROR-gamma; receptor binding; therapeutic target; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Our preliminary results have shown a direct suppression of IL-17 by 1,25(OH)2D3 as well as reversal of paralysis and inhibition of progression of EAE [a murine model of multiple sclerosis (MS)] by 1,25(OH)2D3 which is associated with an inhibition of IL-17. We propose to examine the mechanisms involved. We hypothesize that understanding the mechanisms involved will result in new concepts in our understanding of the interaction between the vitamin D endocrine system and the immune system that may suggest therapeutic targets for the control of MS and other TH17 dependent inflammatory diseases including inflammation induced bone loss. In Specific Aim 1 we will examine the effect of in vivo treatment of EAE mice with 1,25(OH)2D3 on the production of IL-17 and other cytokines (brains and spinal cords as well as splenocytes and lymph nodes will be isolated from EAE mice and the effect of 1,25(OH)2D3 on the production of various cytokines including those produced by TH17 cells (IL-17A, IL-17F, IL-21, IL-22), TH2 cells (IL-4, IL-5), regulatory T cells (IL-10 and TGF?) and innate immune cells (IL-23, IL-12, IL6 and the anti-inflammatory cytokine, IL-27) will be assessed. In preliminary results we noted for the first time that 1,25(OH)2D3 has a direct inhibitory effect on activated IL-17 expression and transcription. The mechanisms involved will be examined (1,25(OH)2D3 may mediate this repression by inhibiting activation mediated by NFAT, Runx1 and ROR gamma transcription factors). Genome-wide analysis of NFAT, Runx1 and vitamin D receptor (VDR) binding sites in CD4+T cell DNA isolated from EAE mice treated with vehicle or 1,25(OH)2D3 using ChIP-seq will also be done. These studies will enable us to identify new target genes and to assess how functional relationship among genes involved in immune function may be altered after 1,25(OH)2D3 treatment. These studies would provide mechanisms for the reversal of paralysis by 1,25(OH)2D3. It is possible that the mechanisms we identify may reflect more general mechanisms involved in a therapeutic role of 1,25(OH)2D3 in the control of pathological immune responses. In Specific Aim 2, since clinical studies are being done treating MS patients with high dose vitamin D, we also propose to examine the effect of high dose dietary vitamin D on paralysis, on the progression of EAE and the production of IL-17 and other cytokines. These studies provide a unique opportunity to combine the expertise of the Steinman lab in multiple sclerosis and immunology and the Christakos lab in vitamin D to increase our understanding of the interaction between the vitamin D endocrine system and the immune system. Findings from these studies may suggest new therapeutic targets and treatment strategies for MS and other TH17 dependent inflammatory diseases. This application is appropriate for the R21 mechanism which supports projects that "involve considerable risk but may lead to a breakthrough in a particular area that could have a major impact on a field of biomedical or clinical research." PUBLIC HEALTH RELEVANCE: An increased understanding of the interaction between the vitamin D endocrine system and the immune system, with a focus on IL-17, a central player in the mammalian immune system, may suggest possible therapeutic targets and treatment strategies for the control of MS and other TH17 dependent inflammatory diseases, including inflammation induced bone loss.

描述（由申请人提供）：我们的初步结果显示 1,25(OH)2D3 可以直接抑制 IL-17，并且 1,25(OH)2D3 可以逆转麻痹并抑制 EAE（多发性硬化症 (MS) 的小鼠模型）的进展，而 1,25(OH)2D3 与 IL-17 的抑制有关。我们建议研究所涉及的机制。我们假设，了解所涉及的机制将为我们理解维生素 D 内分泌系统和免疫系统之间的相互作用带来新概念，这可能会为控制多发性硬化症和其他 TH17 依赖性炎症性疾病（包括炎症引起的骨质流失）提供治疗靶点。在具体目标 1 中，我们将检查用 1,25(OH)2D3 体内治疗 EAE 小鼠对 IL-17 和其他细胞因子产生的影响（将从 EAE 小鼠中分离出脑和脊髓以及脾细胞和淋巴结，以及 1,25(OH)2D3 对各种细胞因子产生的影响，包括 TH17 细胞产生的细胞因子（IL-17A、 将评估 IL-17F、IL-21、IL-22）、TH2 细胞（IL-4、IL-5）、调节性 T 细胞（IL-10 和 TGF？）和先天免疫细胞（IL-23、IL-12、IL6 和抗炎细胞因子 IL-27）。在初步结果中，我们首次注意到 1,25(OH)2D3 具有直接 对激活的IL-17表达和转录的抑制作用。将检查所涉及的机制（1,25(OH)2D3 可能通过抑制 NFAT、Runx1 和 ROR gamma 转录因子介导的激活来介导这种抑制）。对从接受载体或治疗的 EAE 小鼠中分离的 CD4+T 细胞 DNA 中的 NFAT、Runx1 和维生素 D 受体 (VDR) 结合位点进行全基因组分析 还将使用 ChIP-seq 进行 1,25(OH)2D3。这些研究将使我们能够识别新的靶基因，并评估参与免疫功能的基因之间的功能关系在 1,25(OH)2D3 治疗后如何改变。这些研究将提供 1,25(OH)2D3 逆转麻痹的机制。我们确定的机制可能反映了涉及治疗作用的更普遍的机制 1,25(OH)2D3 在控制病理免疫反应中的作用。在具体目标 2 中，由于正在进行使用高剂量维生素 D 治疗 MS 患者的临床研究，我们还建议检查高剂量膳食维生素 D 对瘫痪、EAE 进展以及 IL-17 和其他细胞因子产生的影响。这些研究提供了一个独特的机会，将斯坦曼实验室在多发性硬化症和多发性硬化症方面的专业知识结合起来。 免疫学和 Christakos 维生素 D 实验室，以增加我们对维生素 D 内分泌系统和免疫系统之间相互作用的了解。这些研究的结果可能为 MS 和其他 TH17 依赖性炎症性疾病提供新的治疗靶点和治疗策略。该申请适用于R21机制，该机制支持“涉及相当大风险，但可能在特定领域取得突破，从而对某个领域产生重大影响”的项目。 生物医学或临床研究。” 公共健康相关性：加深对维生素 D 内分泌系统和免疫系统之间相互作用的了解，重点关注哺乳动物免疫系统中的核心角色 IL-17，可能会为控制 MS 和其他 TH17 依赖性炎症性疾病（包括炎症引起的骨质流失）提出可能的治疗靶点和治疗策略。