Role of CCL19/ 21 chemokine in the development of experimental autoimmune encephalomyelitis

实验性自身免疫性脑脊髓炎(EAE)是多发性硬化症的一种动物模型。我们利用本实验室发现的CCL19/21(淋巴T细胞缺失：PLT)表达缺失的突变小鼠，研究了CCL21/19趋化因子在免疫应答调节中的作用。在调查中，我们发现这些突变小鼠对EAE的诱导具有抵抗力。在本研究中，我们对EAE的耐药机制进行了分析，并获得了以下结果：(1)最近发现，Th-17细胞而不是Th-1细胞与EAE的发生有关。在PLT小鼠中，髓鞘少突胶质细胞糖蛋白(MOG)35-55肽在CFA中免疫后不能分化Th-17细胞，从而在野生型(WT)小鼠中诱导Th-17细胞和EAE。(2)IL-17的产生需要IL-6、转化生长因子-β和IL-23。当引流淋巴结细胞孵育时，PLT小鼠和WT小鼠的淋巴细胞培养上清液中检测到IL-6和TGF-β，(3)在PLT小鼠引流淋巴结的CD4T细胞培养中加入IL-23诱导产生IL-17。(4)在PLT小鼠引流淋巴结的CD4T细胞培养中加入CCL21趋化因子不能有效地诱导IL-17的产生。(5)纯化的CD11c树突状细胞在CCL21存在的情况下产生IL-23。(6)CCR7缺陷小鼠的CD11c树突状细胞即使在CCL21存在的情况下也不产生IL-23。这一结果提示在PLT小鼠中由于缺乏IL-23而没有诱导细胞，这是由于CCR7在缺乏CCL21/19趋化因子表达的小鼠身上缺乏刺激所致。我们的下一个项目是开发通过操纵IL-23或CCL21/19趋化因子来治疗EAE的程序。

Experimental autoimmune encephalomyelitis (EAE) in mouse is a model of multiple sclerosis. We have investigated the role of CCL21/19 chemokine in the regulation of immune response, using mutant mouse lacking the expression of CCL19/21 (paucity of lymph node T cells: plt) which was found in our laboratory. During investigation, we found that these mutant mice are resistant to the induction of EAE. In the present study, we analyzed the mechanisms for the resistance, and obtained following results.(1) Recently, it has been established that Th-17 cells other than Th-1 cells are responsible to the development of EAE. In plt mice Th-17 cells did not differentiated after immunization with myelin-oligodendrocyte glycoprotein (MOG) 35-55 peptide in CFA, which induced Th-17 cells and EAE in wild type (WT) mice.(2) IL-6, TGF-beta and IL-23 are required for the production of IL-17. When draining lymph node cells were incubated, IL-6 and TGF-beta were detected in the culture supernatant of the lymph node cells from plt mice similarly to that from WT mice, IL-23 was very low.(3) Addition of IL-23 to the culture of CD4+ T cells from draining lymph nodes of plt mice induced production of IL-17.(4) The addition of CCL21 chemokine to the culture of CD4+ T cells from draining lymph nodes of plt mice was not effective to the induction of IL-17 production.(5) Purified CD11c+ dendritic cells produced IL-23 in the presence of CCL21.(6) CD11c+ dendritic cells from CCR7-deficient mice did not produce IL-23 even when CCL21 was present.These results suggested that in plt mice Th-17 cells were not induced due to the lack of IL-23, which was resulted from the deficient stimulation of CCR7 in the mice lacking the expression of CCL21/19 chemokine.Our next project is developing the procedures to treat EAE by manipulating IL-23 or CCL21/19 chemokine.