LEISHMANIA INFECTION IN BALB/C IL4 NEG AND IL4R NEG MICE

描述(改编自应用摘要)：白介素4(IL-4)在 促进幼稚T细胞分化为IL-4的重要作用 分泌Th2细胞。Th1(干扰素)细胞因子应答与Th2的平衡 体内的反应被认为与几种传染病有关， 过敏反应。用于研究Th1/Th2的体内原型模型 应对措施是感染原生动物寄生虫利什曼原虫。感染 易感BALB/c小鼠诱生强IL-4和Th2相关细胞因子 反应，但L.在耐药品系小鼠中的主要感染与 有Th1细胞因子的特征。这项研究的长期目标是研究 IL-4在Th2应答中的作用，特别是在确定 BALB/c小鼠对梅毒乳杆菌的敏感性。为此，基因纯净 BALB/c白介素4和白介素4R缺陷小鼠株系是通过基因重组获得的。 以BALB/c胚胎干细胞系为靶点。这些老鼠的感染有 显示不同寄生虫亚株的敏感性差异和 表明至少有一些大白菜有其他的途径 寄生虫菌株在没有IL-4的情况下逃避免疫机制。目标是 这项拟议的研究的目的是确定允许 亚株L.main LV39继续在IL-4-/-和IL-4R中致病 -/-老鼠。假设是诱导了除IL-4或IL-13以外的其他因子 在IL-4R-/-小鼠体内，未见IR173的表达。为了解释 体内抗IL-4治疗与抗IL-4治疗结果的差异 基因缺陷的小鼠，假设是抗IL-4影响Th2 反应以及细胞的渗透。在特定目标1中，细胞因子 由LV39和IR173感染引起的特征将在 在耳部皮肤感染模型中接种疫苗的景象。在具体目标2中， IL-10的代偿作用将通过在体内中和IL-10来解决 感染BALB/c IL-10x IL-4R-/-双基因敲除小鼠 LV 39.特异靶向3、抗IL-4治疗对细胞 渗透性将在皮肤感染模型中进行测试。这些研究将 提供对不同主要乳杆菌寄生虫特性的新见解和 将在总体上提供Th1/Th2范式的替代理论。这些 研究还将导致对抗IL-4作用的新解释 体内治疗。

DESCRIPTION (adapted from application abstract): Interleukin-4 (IL-4) plays an important role in promoting the differentiation of naive T cells into IL-4- secreting Th2 cells. The balance of Th1 (IFN) cytokine responses versus Th2 responses in vivo is thought to be involved in several infectious diseases and allergic responses. The prototypic in vivo model used to study Th1/Th2 responses is infection with the protozoan parasite Leishmania major. Infection of susceptible BALB/c mice induces strong IL-4 and Th2-associated cytokine responses, but L. major infection in resistant strains of mice is associated with a Th1 cytokine profile. The long-term goal of this research is to study the role of IL-4 in Th2 responses, and specifically, in determining susceptibility to L. major in BALB/c mice. To that end, genetically pure BALB/c IL-4 and IL-4R deficient mouse strains were generated through gene- targeting in BALB/c embryonic stem cell lines. Infection of these mice have revealed differences in susceptibility depending on the parasite substrain and indicated that there are alternative pathways for at least some L. major parasite strains to escape immune mechanisms in the absence of IL-4. The goal of the proposed research is to identify the mechanism that allows the substrain L. major LV39 to continue to cause disease in both IL-4-/- and IL-4R -/- mice. The hypothesis is that a factor other than IL-4 or IL-13 is induced by L. major LV39, but not by IR173, in IL-4R -/- mice. In order to explain the difference between anti-IL-4 treatment in vivo and the results with genetically-deficient mice, the hypothesis is that anti-IL-4 affects Th2 responses as well as cellular infiltration. In Specific Aim 1, the cytokine profiles induced by LV39 and IR173 infections will be characterized at the sight of inoculation in an ear dermal model of infection. In Specific Aim 2, the role of IL-10 compensation will be addressed by neutralizing IL-10 in vivo and infecting BALB/c IL-10 x IL-4R -/- double knockout mice with L. major LV39. In Specific Aim 3, the action of anti-IL-4 treatment on cellular infiltration will be tested in a dermal infection model. These studies will provide novel insights into the properties of different L. major parasites and will offer alternative theories to the Th1/Th2 paradigm in general. These studies also will lead to new interpretations of the action of anti-IL-4 treatment in vivo.