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

小鼠实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症的模型。我们利用实验室发现的缺乏CCL19/21（淋巴结T细胞缺乏：plt）表达的突变小鼠，研究了CCL21/19趋化因子在免疫反应调控中的作用。在研究过程中，我们发现这些突变小鼠对EAE的诱导具有抗性。在本研究中，我们分析了抗性的机制，得到了以下结果。(1)近年来，已经确定除Th-1细胞外，Th-17细胞也参与EAE的发生。在野生型（WT）小鼠中，用CFA中的髓鞘-少突胶质细胞糖蛋白（MOG） 35-55肽免疫后，Th-17细胞未分化。(2) IL-17的生成需要IL-6、tgf - β和IL-23。当引流淋巴结细胞孵育时，在plt小鼠的淋巴结细胞培养上清中检测到IL-6和tgf - β，与WT小鼠相似，IL-23很低。(3)在plt小鼠引流淋巴结CD4+ T细胞培养中加入IL-23诱导IL-17的产生。(4)在plt小鼠引流淋巴结CD4+ T细胞培养中加入CCL21趋化因子对IL-17的产生无诱导作用。(5)纯化的CD11c+树突状细胞在CCL21存在下产生IL-23。(6) ccr7缺陷小鼠的CD11c+树突状细胞即使存在CCL21也不产生IL-23。这些结果表明，在plt小鼠中，由于缺乏IL-23， th17细胞未被诱导，这是由于缺乏CCL21/19趋化因子表达的小鼠缺乏CCR7刺激导致的。我们的下一个项目是开发通过操纵IL-23或CCL21/19趋化因子治疗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.