Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes
Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes
复制标题
DOI：
10.1111/j.1749-6632.2003.tb06057.x
复制
发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Adorini, L
中科院分区：
文献类型：
--
作者：
Adorini, L
树突状细胞（Dendritic cells，DCs）不仅能诱导T细胞活化，还能调节T细胞活化。1，25-二羟基维生素D-3 [1，25-（OH）（2）D-3]诱导具有致耐受性表型的DC，其特征在于CD40、CD80和CD86共刺激分子的表达降低、低IL-12和增强的IL-10分泌。我们发现，1，25-（OH）（2）D-3短期处理诱导了对完全不匹配的小鼠胰岛同种异体移植物的耐受性，并且这种耐受性对供体型脾细胞的挑战是稳定的，并且允许接受供体型血管化心脏移植物。这种作用通过共同施用霉酚酸酯（A4 MF）而增强，霉酚酸酯是T和B细胞增殖的选择性抑制剂，其对DC也具有类似于1，25-（OH）（2）D-3的作用。移植物接受性与1型CD 4（+）和CD 8（+）细胞发育受损以及脾脏和引流淋巴结中表达CD 152的CD 4（+）CD 25（+）调节细胞百分比增加相关。移植耐受小鼠的CD4（+）CD25（+）细胞可保护100%的同系受体免于胰岛移植排斥反应。能够抑制对胰腺自身抗原的T细胞应答并显著延迟由致病性CD4（+）CD25（-）细胞引起的疾病转移的CD4（+）CD25（+）细胞也可通过用选定的维生素D受体（VDR）配体处理成年非肥胖糖尿病（NOD）小鼠来诱导。这种治疗阻止胰岛炎和Th1细胞浸润的进展，并在非高钙剂量下抑制糖尿病的发展。通过短期口服诱导耐受原性DC的小分子有机化合物（如VDR配体），CD4（+）CD25（+）调节性T细胞能够介导移植耐受并阻止1型糖尿病的发展，这表明这种方法可能具有临床应用价值。
Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25-Dihydroxyvitaniin D-3 [1,25-(OH)(2)D-3] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 co-stimulatory molecules, low IL-12, and enhanced IL-10 secretion. We have found that a short treatment with 1,25-(OH)(2)D-3 induces tolerance to fully mismatched mouse islet allografts, and that this tolerance is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. This effect is enhanced by co-administration of mycophenolate mofetil (A4MF), a selective inhibitor of T and B cell proliferation, that also has effects similar to 1,25-(OH)(2)D-3 on DCs. Graft acceptance is associated with impaired development of type 1 CD4(+) and CD8(+) cells and an increased percentage of CD4(+)CD25(+) regulatory cells expressing CD152 in the spleen and in the draining lymph node. Transfer of CD4(+)CD25(+) cells from tolerant mice protects 100% of the syngeneic recipients from islet allograft rejection. CD4(+)CD25(+) cells that are able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells are also induced by treatment of adult nonobese diabetic (NOD) mice with a selected vitamin D receptor (VDR) ligand. This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non-hypercalcemic doses. The enhancement of CD4(+)CD25(+) regulatory T cells able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with small organic compounds that induce tolerogenic DCs, like VDR ligands, suggests possible clinical applications of this approach.