Vitamin D and NKT Cell Regulation of Multiple Sclerosis

维生素 D 和 NKT 细胞对多发性硬化症的调节

• 批准号: 8249888
• 负责人: MARGHERITA T CANTORNA
• 金额: $ 31.1万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249888
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmunity; CD8B1 gene; Cells; Cessation of life; Child; Childhood; Complement; Data; Developed Countries; Development; Diet; Disease; Dose; Environment; Experimental Autoimmune Encephalomyelitis; Exposure to; Goals; Homeostasis; Human; Hygiene; Immune; Immune response; Immune system; Immunity; In Vitro; Incidence; Infant; Knockout Mice; Life; Link; Mediating; Misinformation; Molecular; Molecular Target; Multiple Sclerosis; Mus; Patients; Play; Pollution; Population; Prevention; Principal Investigator; Property; Regulation; Regulatory T-Lymphocyte; Role; Serum; Shapes; Staging; Sun Exposure; T cell response; T-Lymphocyte; Testing; Thymus Gland; Universities; Vitamin D; Vitamin D3 Receptor; Vitamins; Work; cellular targeting; cytokine; dietary supplements; experience; gastrointestinal; immune function; in utero; in vivo; inhibitor/antagonist; killer T cell; microbial; novel; pediatric department; prenatal; prevent; programs; public health relevance; response; season of birth; thymocyte

DESCRIPTION (provided by applicant): There are profound effects of vitamin D on immune function. There is data to suggest that increased levels of vitamin D (either through diet, supplements or sunlight exposure) are beneficial for multiple sclerosis (MS) patients. In addition, active vitamin D (1,25(OH)2D3) treatment of experimental autoimmune encephalomyelitis (EAE) blocks the development of disease. In the first year of life infants undergo considerable fluctuation in their circulating vitamin D (25(OH)D3) levels. We hypothesize that early changes in vitamin D have profound effects on the thymus such that iNKT cells fail to develop and as a result autoimmune diseases like MS are more likely to develop. iNKT cells require adequate vitamin D in utero and the expression of the vitamin D receptor (VDR) for both development and function. iNKT cells have been implicated as inhibitors and regulatory cells in EAE and MS. The hypothesis to be tested is that vitamin D regulates iNKT cells and as a result is important for shaping the developing immune response and preventing and controlling the development of autoimmunity. The goals of this proposal are to determine the molecular mechanisms underlying vitamin D and the VDRs effects on iNKT cells. The aims are to determine the plasticity of the iNKT cell response as a function of changes in vitamin D status, determine the role of vitamin D in the thymus for iNKT cell development, determine how changes in vitamin D affect proliferation, survival and death of iNKT cells, and to determine the role of active vitamin D (1,25(OH)2D3) regulation of iNKT cells in suppression of EAE and whether changes in vitamin D status in vivo or 1,25(OH) 2D3 in vitro regulates human NKT cell expansion and function. NKT cells are novel targets in MS and a better understanding of the mechanisms by which their development and function are regulated by vitamin D and 1,25(OH)2D3 would be critical for manipulating NKT cells therapeutically. PUBLIC HEALTH RELEVANCE: There is at present a great deal of misinformation about vitamin D and vitamin D supplements as immune system modulators in the public forum. Identifying the cellular and molecular targets of vitamin D in the immune system is important so that rational decisions about the use of vitamin D supplements and/or active vitamin D compounds to manipulate the immune system and prevent or treat autoimmune diseases like multiple sclerosis.

描述(申请人提供)：维生素D对免疫功能有深远的影响。有数据表明，增加维生素D水平(通过饮食、补充剂或阳光暴晒)对多发性硬化症(MS)患者是有益的。此外，活性维生素D(1，25(OH)2D3)治疗实验性自身免疫性脑脊髓炎(EAE)阻止了疾病的发展。在婴儿出生的第一年，他们循环中的维生素D(25(OH)D3)水平有相当大的波动。我们假设，维生素D的早期变化对胸腺有深远的影响，以至于iNKT细胞无法发育，因此更有可能发展成像MS这样的自身免疫性疾病。INKT细胞在子宫中需要足够的维生素D，并且需要维生素D受体(VDR)的表达才能发育和发挥功能。INKT细胞在EAE和MS中被认为是抑制和调节细胞，有待检验的假设是维生素D调节iNKT细胞，因此对于形成发育中的免疫反应和预防和控制自身免疫的发展具有重要意义。这项建议的目标是确定维生素D和VDR对iNKT细胞影响的分子机制。其目的是确定iNKT细胞反应的可塑性作为维生素D状态变化的函数，确定维生素D在胸腺中对iNKT细胞发育的作用，确定维生素D的变化如何影响iNKT细胞的增殖、存活和死亡，并确定活性维生素D(1，25(OH)2D3)调节iNKT细胞在抑制EAE中的作用，以及体内维生素D状态的变化或体外1，25(OH)2D3是否调节人NKT细胞的增殖和功能。NKT细胞是多发性硬化症的新靶点，更好地理解维生素D和1，25(OH)2D3调节其发育和功能的机制将是操纵NKT细胞治疗的关键。 与公共健康相关：目前在公共论坛上有大量关于维生素D和维生素D补充剂作为免疫系统调节剂的错误信息。确定免疫系统中维生素D的细胞和分子靶点非常重要，以便合理决定是否使用维生素D补充剂和/或活性维生素D化合物来操纵免疫系统，预防或治疗多发性硬化症等自身免疫性疾病。