Lymphoid Chemokines in Autoimmune Encephalomyelitis

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种中枢神经系统（CNS）炎症性脱髓鞘疾病，被广泛用作多发性硬化症（MS）的动物模型。在这项提议中，我们将测试一个新的EAE免疫发病机制模型，重点关注驱动中枢神经系统慢性炎症的因素。在初步研究中，我们发现CD11c（树突状细胞）在EAE期间在白质浸润中积聚。此外，小鼠脊髓中的淋巴样趋化因子CCL19、CCL21和CXCL13在EAE发病时上调，并在疾病进展过程中稳步升高。基于这些发现，我们提出以下假设：(i) CNS CD11c(细胞在GM-CSF的影响下从驻留的小胶质细胞分化，继而通过浸润的T细胞分泌，（ii） CD11c(细胞随后分泌促炎细胞因子（如IL-12）和趋化因子，包括CXCL13、CCL19和CCL21；（iii） CXCL13、CCL19和CCL21向中枢神经系统招募白细胞，并帮助形成血管周围浸润的细胞组成；（iv）淋巴样趋化因子的局部产生也会触发淋巴样新生（淋巴结样结构的形成）和中枢神经系统内B细胞的活化；(v)中枢神经系统淋巴样趋化因子最终导致临床EAE的严重程度和慢性程度。我们将使用新颖的实验方法测试上述假设方案的每一步。在目的1中，我们将与gfp转基因或GM-CSF缺陷小鼠构建骨髓嵌合体，以确定CNS CD11c细胞的谱系。在目标2和目标3中，将比较免疫正常小鼠和淋巴趋化因子缺陷小鼠对过继转移EAE的易感性、白细胞向白质病变的募集、中枢神经系统内淋巴样细胞新生和B细胞活化。我们的研究可能为自身免疫性脱髓鞘的发病机制提供新的见解，并导致创新的治疗方法，如对抗淋巴样趋化因子和/或阻断中枢神经系统树突状细胞积累的试剂。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) that is widely used as an animal model of multiple sclerosis (MS). In this proposal, we will test a novel model of the immunopathogenesis of EAE focusing on factors that drive chronic inflammation in the CNS. In preliminary studies we demonstrated that CD11c ( dendritic-like cells accumulate in white matter infiltrates during EAE. Furthermore, the lymphoid chemokines, CCL19, CCL21 and CXCL13, are upregulated in spinal cords of mice at EAE onset and steadily rise during disease progression. Based on these findings, we propose the following hypotheses: (i) CNS CD11c ( cells differentiate from resident microglia under the influence of GM-CSF that, in turn, is secreted by infiltrating T cells, (ii) CD11c ( cells then secrete proinflammatory cytokines (such as IL-12) and chemokines including CXCL13, CCL19 and CCL21; (iii) CXCL13, CCL19 and CCL21 act to recruit leukocytes to the CNS and help shape the cellular composition of perivascular infiltrates; (iv) local production of lymphoid chemokines also triggers lymphoid neogenesis (the development of lymph node-like structures) and B cell activation within the CNS; (v) ultimately, CNS lymphoid chemokines contribute to the severity and chronicity of clinical EAE. We will test each step of the above hypothetical scheme using novel experimental approaches. In Aim 1 we will construct bone marrow chimeras with GFP-transgenic or GM-CSF deficient mice to determine the lineage of CNS CD11c ( cells. In Aims 2 and 3, immunocompetent and lymphoid chemokine deficient mice will be compared with regard to susceptibility to adoptively transferred EAE, recruitment of leukocytes to white matter lesions, and lymphoid neogenesis and B cell activation within the CNS. Our studies might provide new insights into the pathogenesis of autoimmune demyelination and lead to innovative therapies such as reagents that antagonize lymphoid chemokines and/or block CNS dendritic cell accumulation.