Mechanisms of mast cell influence on EAE disease course

描述（由申请人提供）：CD4 + T细胞在启动与多发性硬化症（MS）和MS啮齿动物模型实验性过敏性脑脊髓炎（EAE）相关的自身免疫破坏中起着至关重要的作用。然而，多种其他炎症细胞，包括B细胞和巨噬细胞，有助于导致在这种疾病综合征中观察到的不同程度的髓鞘和轴突损伤的事件。肥大细胞以其在皮肤和呼吸道的过敏反应中所起的作用而闻名，在全身许多组织中都有广泛的分布。与此应用相关的是，这些细胞普遍存在于初始T细胞活化的部位，如脾脏和淋巴结。此外，它们与血管和神经的密切联系以及肥大细胞可以产生的大量免疫调节介质使它们成为深刻影响免疫功能的可行候选者。利用髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE模型，我们最近证明肥大细胞缺陷小鼠表现出延迟发病和较轻的疾病。用野生型骨髓肥大细胞重建肥大细胞群，这一过程不能纠正这些动物的其他血液学异常，但可以恢复对严重疾病的易感性。令人惊讶的是，这种疾病易感性的恢复发生在没有检测到中枢神经系统肥大细胞重构的情况下，揭示了肥大细胞在外周的作用。这些发现不排除肥大细胞直接影响肥大细胞能态动物中枢神经系统炎症事件的可能性。然而，它们确实阐明了一个模型，用于研究肥大细胞如何影响自身免疫T细胞反应的产生和特征，而不受任何中枢神经系统的影响。在本应用中，我们拟通过实验确定肥大细胞对病程的影响位点，并探讨肥大细胞发挥其影响的机制。具体目的如下：1)确定肥大细胞在疾病中的激活模式；2)观察EAE中肥大细胞调节的淋巴细胞特异性免疫反应；3)确定肥大细胞对疾病影响的介质

DESCRIPTION (provided by applicant): It is well established that CD4 + T cells are of central importance in initiating the autoimmune destruction associated with multiple sclerosis (MS) and the rodent model of MS, experimental allergic encephalomyelitis (EAE). However, a variety of other inflammatory cells, including B cells and macrophages, contribute to the events that lead to the varying degrees of myelin and axonal damage observed in this disease syndrome. Mast cells, best known for their role in allergic responses in the skin and respiratory tract, exhibit widespread distribution in many tissues throughout the body. Relevant to this application, these cells are prevalent within sites of initial T cell activation such as the spleen and lymph node. In addition, their intimate association with blood vessels and nerves and the plethora of immunoregulatory mediators that can be produced by mast cells make them viable candidates for profoundly influencing immune function. Using the myelin oligodendrocyte glycoprotein (MOG)-induced model of EAE, we recently demonstrated that mast cell-deficient mice exhibit delayed onset and less severe disease than their wild type littermates. Reconstitution of the mast cell population with wild type bone marrow mast cells, a procedure that does not correct other hematological abnormalities in these animals, restores the susceptibility to severe disease. Surprisingly, this restoration of disease susceptibility occurs without detectable reconstitution of mast cells in the CNS, revealing a role for mast cells in the periphery. These findings do not rule out the possibility that mast cells directly influence inflammatory events in the CNS in mast cell competent animals. However, they do illuminate a model for examining how mast cells can influence the generation and character of the autoimmune T cell response, independent of any CNS effects. In this application, we propose experiments to determine the sites of mast cell influence on disease course and to explore the mechanism through which mast cells exert their influence. The specific aims are as follows: 1) To determine the modes of mast cell activation in disease; 2) To characterize specific mast cell-regulated lymphoctye immune responses in EAE; 3) To determine the mediators that confer mast cell influence on disease