Mechanisms of mast cell influence on EAE disease course

肥大细胞对EAE病程影响的机制

• 批准号: 7162626
• 负责人: Melissa A Brown
• 金额: $ 25.95万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162626
• 关键词: Affect; Allergic; Animals; Antigens; Autoimmune Process; B-Lymphocytes; Blood - brain barrier anatomy; Blood Vessels; Bone Marrow; Breeding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Surface Proteins; Cell physiology; Cells; Dendritic Cells; Disease; Disease susceptibility; Encephalomyelitis; Endopeptidases; Epitopes; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Frequencies; Generations; Genes; Histamine; Histamine Release; Homing; Immune response; Immunization; Inflammatory; Interleukin-10; Interleukin-4; Lead; Little' s Disease; Lymphocyte; Lymphoid; Mediator of activation protein; Melissa; Methods; Modeling; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Myelin Associated Glycoprotein; Myelin Sheath; Nerve; Numbers; Organ; Outcome; Peptide Hydrolases; Personal Satisfaction; Phase; Phenotype; Play; Population; Predisposition; Procedures; Production; Regulation; Relapse; Relative (related person); Research Personnel; Respiratory System; Rodent Model; Role; SJL Mouse; Secondary to; Severities; Site; Skin; Spleen; Staging; Study models; Syndrome; T cell regulation; T-Cell Activation; T-Lymphocyte; TNFSF5 gene; Testing; Tissues; Transgenic Organisms; autoreactive T cell; base; chemokine; cytokine; immune function; lymph nodes; macrophage; mast cell; migration; oligodendrocyte-myelin glycoprotein; programs; receptor; reconstitution; research study; response; restoration; trafficking

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

描述（由申请人提供）：已经确定，CD 4 + T细胞在启动与多发性硬化（MS）和MS啮齿动物模型（实验性过敏性脑脊髓炎（EAE））相关的自身免疫性破坏中具有核心重要性。然而，多种其他炎性细胞，包括B细胞和巨噬细胞，促成导致在该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，最为人所知的是它们在皮肤和呼吸道中的过敏反应中的作用，在整个身体的许多组织中表现出广泛的分布。与本申请相关，这些细胞在初始T细胞活化的部位如脾和淋巴结内普遍存在。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过多的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。使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，肥大细胞缺陷型小鼠表现出延迟发病和较轻的疾病比野生型同窝出生。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学异常，但会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在CNS中没有可检测到的肥大细胞重建的情况下发生，揭示了肥大细胞在外周中的作用。这些发现并不排除肥大细胞直接影响肥大细胞活性动物CNS炎症事件的可能性。然而，他们确实阐明了一个模型，用于检查肥大细胞如何影响自身免疫T细胞反应的产生和特征，而不依赖于任何CNS效应。在这个应用中，我们提出了实验来确定肥大细胞对疾病过程的影响的网站，并探讨肥大细胞发挥其影响的机制。本研究的主要目的如下：1）确定肥大细胞在疾病中的激活模式; 2）表征肥大细胞调节的特异性淋巴细胞免疫应答; 3）确定肥大细胞对疾病影响的介质