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

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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.