Mechanisms of mast cell influence on EAE disease course

描述(由申请人提供)：众所周知，在启动与多发性硬化症(MS)和多发性硬化症(MS)啮齿动物模型相关的自身免疫破坏(实验性变态反应性脑脊髓炎(EAE))过程中，CD4+T细胞起着核心作用。然而，包括B细胞和巨噬细胞在内的各种其他炎症细胞参与了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过敏反应中的作用而闻名，在全身许多组织中广泛分布。与这一应用相关的是，这些细胞普遍存在于T细胞最初激活的部位，如脾和淋巴结。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过多的免疫调节介质，使它们成为深刻影响免疫功能的候选细胞。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比它们的野生型小鼠表现出起病延迟和病情轻的特点。用野生型骨髓肥大细胞重建肥大细胞群，这一过程不会纠正这些动物的其他血液异常，恢复了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时，中枢神经系统中的肥大细胞没有检测到重建，揭示了周围肥大细胞的作用。这些发现不排除肥大细胞直接影响肥大细胞能胜任的动物中枢神经系统炎症事件的可能性。然而，他们确实阐明了一个模型，用来检验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。在这一应用中，我们提出了一些实验，以确定肥大细胞影响疾病进程的位置，并探讨肥大细胞影响疾病过程的机制。其具体目的如下：1)确定疾病中肥大细胞的激活方式；2)表征EAE中特定的肥大细胞调节的淋巴免疫反应；3)确定肥大细胞影响疾病的介质。

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