Regulation of Gender Dependent EAE Susceptibility

描述（由申请人提供）：本申请探索了在Th 1介导的CNS自身免疫性疾病中使用SJL小鼠的性别和年龄依赖性自身免疫性疾病抗性/易感性模型中通过CD 25 + T细胞和NK 1.1+细胞对APC活性的稳态调节。诱发实验性自身免疫性脑脊髓炎（EAE）的致脑炎性Th 1细胞在所有年龄的雌性和成熟雄性（>12周龄）中被激活。相比之下，Ag特异性Th 2细胞在年轻成年（6周龄）男性中被激活，导致EAE抗性。来自抗性男性而非年龄匹配的女性的CD 4 + CD 25 + T细胞的消耗将证明CD 25 +T细胞抑制Th 1活化。连续转移将证明来自抗性6周雄性的CD 25 + T细胞抑制雌性和成熟雄性受体中的EAE。我们的假设，即APC在体内改变CD 4 + CD 25 + T细胞，将通过在来自CD 25+耗尽的6周男性供体的APC的抗性6周男性受体中诱导EAE来测试。在NK1.1 +细胞耗尽或从NK1.1耗尽的抗性供体转移APC后的EAE抗性雄性中也诱导Th 1应答。通过阻断或受体配体和DAP 12 KO小鼠的分析来检查抗性雄性中NK细胞频率增加通过细胞-细胞相互作用改变APC的假设。通过体内和体外方法检测了CD 25 + T细胞、NK细胞和APC之间的三方相互作用，其通过Th 2活化导致EAE抗性。在NK或CD 25 + T细胞耗竭后，分析每种细胞类型对其他两种细胞类型中细胞因子分泌、表面和基因表达的影响。这些实验将提供由性别和年龄调节的单个固定基因型内的细胞-细胞相互作用的机制分析，其最终影响对自身免疫性疾病的抗性或易感性。这些数据还将提供NK和CD 25 + T细胞通过APC功能的改变在抗原遭遇之前影响适应性免疫的第一个证据。

DESCRIPTION (provided by applicant): This application explores the homeostatic regulation of APC activity by CD25+ T cells and NK1.1+ cells in a gender and age dependent autoimmune disease resistance/susceptibility model using SJL mice in a Th1 mediated CNS autoimmune disease. Encephalitogenic Th1 cells inducing experimental autoimmune encephalomyelitis (EAE) are activated in females of all ages and mature males (>12 wks old). By contrast, Ag specific Th2 cells are activated in young adult (6 wk old) males, resulting in EAE resistance. Depletion of CD4 + CD25 + T cells from resistant males, but not age matched females, will demonstrate that CD25+T cells suppress Th1 activation. Adoptive transfers will demonstrate that CD25 + T cells from resistant 6 wk males inhibits EAE in female and mature male recipients. Our hypothesis, that the APC alters the CD4 + CD25 + T cells in vivo will be tested by inducing EAE in resistant 6 wk male recipients of APC derived from CD25 + depleted 6 wk male donors. Th1 responses are also induced in EAE resistant males either depleted of NK1.1 + cells or following APC transfer from NK1.1 depleted resistant donors. The hypothesis that the increased frequency of NK cells in resistant males alters the APC via cell-cell interaction is examined by blockade or receptor ligand and analysis of DAP 12 KO mice. Tripartite interactions between CD25 + T cells, NK cells and APC which lead to EAE resistance via Th2 activation are examined by in vivo and in vitro approaches. The influence of each cell type on cytokine secretion, surface and gene expression in the other two cell types will be analyzed following depletion of either the NK or CD25 + T cells. These experiments will provide a mechanistic analysis of cell-cell interactions within a single fixed genotype regulated by both gender and age which ultimately influence resistance or susceptibility to autoimmune disease. These data will also provide the first evidence that NK and CD25 + T cells influence adaptive immunity prior to antigen encounter via alterations in APC function.