Vitamin D and NKT Cell Regulation of Multiple Sclerosis

描述（由申请人提供）：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，补充剂或阳光照射）对多发性硬化症（MS）患者有益。此外，活性维生素D（1，25（OH）2D 3）治疗实验性自身免疫性脑脊髓炎（EAE）可阻断疾病的发展。在生命的第一年，婴儿的循环维生素D（25（OH）D3）水平经历相当大的波动。我们假设维生素D的早期变化对胸腺有深远的影响，使得iNKT细胞无法发育，因此更有可能发展为MS等自身免疫性疾病。iNKT细胞在子宫内需要足够的维生素D和维生素D受体（VDR）的表达以用于发育和功能。iNKT细胞已被认为是EAE和MS中的抑制剂和调节细胞。待测试的假设是维生素D调节iNKT细胞，因此对于形成发展中的免疫应答以及预防和控制自身免疫的发展是重要的。该提案的目标是确定维生素D和VDRs对iNKT细胞影响的分子机制。目的是确定作为维生素D状态变化的函数的iNKT细胞应答的可塑性，确定维生素D在胸腺中对于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，以及确定活性维生素D的作用（1，25（OH）2D 3）在抑制EAE中对iNKT细胞的调节以及体内维生素D状态或体外1，25（OH）2D 3的变化是否调节人NKT细胞扩增和功能。NKT细胞是MS中的新靶点，更好地了解维生素D和1，25（OH）2D 3调节其发育和功能的机制对于治疗性操纵NKT细胞至关重要。 公共卫生相关性：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。确定维生素D在免疫系统中的细胞和分子靶点非常重要，以便合理决定使用维生素D补充剂和/或活性维生素D化合物来操纵免疫系统并预防或治疗自身免疫性疾病，如多发性硬化症。

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.