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）：我们的初步结果表明，IL-17征至1,25（OH）2d3以及瘫痪和抑制EAE进展的逆转[多发性硬化症（MS）]的逆转和抑制作用1,25（OH）2D3与IL-17抑制有关。我们建议检查涉及的机制。我们假设了解所涉及的机制将在我们理解维生素D内分泌系统与免疫系统之间的相互作用方面产生新的概念，这可能建议控制MS和其他TH17依赖性炎症性疾病，包括炎症引起的骨骼损失。在特定目的1中，我们将研究用1,25（OH）2d3对EAE小鼠的体内治疗对IL-17和其他细胞因子的产生（大脑和脊髓以及脾脏和淋巴结的生产（将与EAE小鼠）分离出1,25（OH）2d3（OH）2D3的效果。 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-23，IL-12，IL6和抗炎性细胞因子，IL-27，IL-27）均可在第3名中进行25。对激活的IL-17表达和转录的抑制作用。也将完成使用芯片序列的1,25（OH）2d3。这些研究将使我们能够鉴定新的靶基因，并评估1,25（OH）2d3处理后参与免疫功能的基因之间的功能关系。这些研究将提供1,25（OH）2d3的瘫痪逆转机制。我们确定的机制可能反映了1,25（OH）2d3在控制病理免疫反应中的治疗作用中涉及的更一般的机制。在特定的目标2中，由于已经完成了高剂量维生素D的MS患者的临床研究，因此我们还建议检查高剂量饮食中维生素D对麻痹，EAE进展以及IL-17和其他细胞因子的产生的影响。这些研究提供了一个独特的机会，可以在多发性硬化症和免疫学中结合Steinman Lab的专业知识以及维生素D的Christakos Lab，以增强我们对维生素D内分泌系统与免疫系统之间相互作用的理解。这些研究的发现可能表明MS和其他依赖性炎症性疾病的新治疗靶标和治疗策略。该应用适用于R21机制，该机制支持“涉及相当大的风险，但可能会导致可能对生物医学或临床研究领域产生重大影响的特定领域的突破”。 公共卫生相关性：对维生素D内分泌系统与免疫系统之间相互作用的相互作用的了解，重点是IL-17（哺乳动物免疫系统中的核心参与者IL-17），可能表明可能控制MS和其他TH17依赖性炎症性疾病，包括炎症诱发的骨骼损失。