The regulation of myeloid cell development and mobilization during autoimmune dem

描述（由申请人提供）：血源性骨髓细胞（巨噬细胞和树突细胞）是多发性硬化（MS）患者和实验性自身免疫性脑脊髓炎（EAE）动物中炎性浸润的主要成分。它们与导致这些疾病残疾的脱髓鞘和轴突丢失有关。然而，对于自身免疫性脱髓鞘疾病期间外周和CNS中的髓样细胞是如何被调节的知之甚少。我们发现，骨髓祖细胞在EAE急性加重之前以加速的速率从骨髓中动员。新输出的Ly 6ChiCD 11b+单核细胞在临床前阶段浸润CNS，并产生CD 11 c +MHC ClassIIhi DC，其在症状阶段构成神经炎性细胞的显著百分比。在目标1中，我们将研究EAE期间骨髓髓样细胞的扩增和动员的细胞因子途径和分子机制。我们的工作假设是，GM-CSF和MIP-1a，髓鞘特异性T细胞诱导，刺激骨髓基质细胞产生G-CSF和CXCL 1/2。这些因素，反过来，激活常驻中性粒细胞分泌蛋白酶，降解趋化因子和粘附分子的螯合造血前体细胞在髓内壁龛的关键。中断该途径中的任何步骤（例如，通过中和G-CSF或通过灭活蛋白酶）将阻止骨髓细胞释放，并最终耗尽复发期间提供CNS浸润细胞来源的外周单核细胞池。在目标2中，我们将研究刺激Ly 6ChiCD 11b+单核细胞在CNS内分化为CD 11 c +MHC IIhi类DC的因素。我们认为，中枢神经系统浸润单核细胞获得髓样树突状细胞的特征，随后直接与髓鞘特异性T细胞的相互作用。将评估候选可溶性因子（如GM-CSF和TNF）和细胞表面分子（如RANKL、CD 40 L和光敏素）的作用。我们的研究很可能为自身免疫过程中驱动致病性骨髓细胞动员和发展的途径提供见解。这些结果有望提示与髓系细胞失调相关的MS新的治疗靶点和生物标志物。

DESCRIPTION (provided by applicant): Blood borne myeloid cells (macrophages and dendritic cells) comprise a major component of the inflammatory infiltrates in patients with multiple sclerosis (MS) and animals with experimental autoimmune encephalomyelitis (EAE). They have been implicated in the demyelination and axonal loss that cause disability in these disorders. However, relatively little is known about how myeloid cells are regulated in the periphery and CNS during autoimmune demyelinating disease. We have found that myeloid progenitor cells are mobilized from the bone marrow at an accelerated rate immediately prior to EAE exacerbations. Newly exported Ly6ChiCD11b+ monocytes infiltrate the CNS during the preclinical stage and give rise to the CD11c+MHC ClassIIhi DC that constitute a significant percent of neuroinflammatory cells during the symptomatic stage. In Aim 1 we will investigate the cytokine pathways and molecular mechanisms underlying the expansion and mobilization of bone marrow myeloid cells during EAE. Our working hypothesis is that GM-CSF and MIP-1a, induced by myelin-specific T cells, stimulate bone marrow stromal cells to produce G-CSF and CXCL1/2. These factors, in turn, activate resident neutrophils to secrete proteases that degrade chemokines and adhesion molecules critical for the sequestration of hematopoietic precursor cells in intramedullary niches. Interruption of any step in this pathway (ex, by neutralizing G-CSF or by inactivating proteases) will prevent myeloid cell release and ultimately exhaust the peripheral monocyte pools that provide a source of CNS infiltrating cells during relapses. In Aim 2 we will investigate the factors that stimulate Ly6ChiCD11b+ monocytes to differentiate into CD11c+MHC Class IIhi DC within the CNS. We propose that CNS infiltrating monocytes acquire characteristics of myeloid dendritic cells consequent to direct interactions with myelin- specific T cells. The roles of candidate soluble factors (such as GM-CSF and TNF) and cell surface molecules (such as RANKL, CD40L and Lymphotoxin-¿) will be assessed. Our studies are likely to provide insights into the pathways driving the mobilization and development of pathogenic myeloid cells during autoimmunity. The results are expected to suggest novel therapeutic targets and biomarkers in MS related to myeloid cell dysregulation.