An Animal Model of Hemophagocytic Lymphohistiocytosis

摘要噬血细胞淋巴组织细胞增多症是一种儿童免疫过度和异常的疾病。 活化，其特征是骨髓严重受损，死亡率接近50%。 几乎所有的HLH患者都严重缺乏T细胞和NK细胞的细胞毒性杀伤，许多 这些患者被发现在编码穿孔素的基因中存在突变。我们写了一本小说 这种疾病的小鼠模型，其中穿孔素缺陷(PRF)小鼠被淋巴细胞攻击 脉络膜脑膜炎病毒(LCMV)。在感染后，PRF小鼠产生的表型几乎与 啊哈。利用这个模型，我们发现HLH型是由异常基因直接驱动的 CD8+T细胞过度产生干扰素-γ。此外，我们还发现来自PRF的DC 小鼠体内病毒抗原含量增加，刺激病毒特异性T细胞的能力增强 感染后的细胞。这些发现暗示DC人群的抗原提呈增加，因为 PRF小鼠干扰素-g过度产生的根本原因，并提示穿孔素正常功能下调 调节抗原呈递。已知多种表达穿孔素的细胞类型与DC相互作用。 为了确定这些人群中的哪些通常会下调DC的刺激，我们有 进行了一系列的细胞耗尽、移植和骨髓移植实验。这些研究 已经发现，表达穿孔素的细胞类型可以影响DC功能和体内干扰素-g CD8+T细胞是发挥这种调节作用的最关键的细胞类型。 根据我们的初步研究，我们假设所选的穿孔素依赖的细胞毒杀伤 由CD8+T细胞产生的树突状细胞限制了抗原进入和/或在DC群体中的持久性，从而 限制免疫激活。为了验证我们的假设，我们将追求以下特定目标：目标1。定义 在LCMV感染后，WT和PRF DC亚群之间的抗原处理和提呈有何不同。目标2。) 确定CD8+T细胞是否是抑制DC刺激功能的主要细胞类型 穿孔素依赖机制。这个项目将有助于更好地理解细胞毒如何发挥作用。 调节免疫反应，改善HLH症患者的治疗方法 其他免疫病理障碍。

Hemophagocytic lymphohistiocytosis (HLH) is a childhood disorder of excessive and abnormal immune activation, characterized by severe damage to the bone marrow, and a mortality rate approaching 50%. Nearly all patients with HLH have a severe deficiency of cytotoxic killing by T and NK cells, and many of these patients have been found to harbor mutations in the gene encoding perforin. We developed a novel murine model of this disorder, in which perforin deficient (prf) mice are challenged with lymphocytic choriomeningitis virus (LCMV). Following infection, prf mice develop a phenotype that is nearly identical to HLH. Using this model, we have discovered that the HLH phenotype is directly driven by the abnormal overproduction of interferon gamma (IFN-g) by CD8+ T cells. Additionally, we have found that DC's from prf mice harbor increased amounts of viral antigen and acquire increased capacity to stimulate virus-specific T cells after infection. These findings implicate increased antigen presentation by DC populations as the underlying cause of IFN-g overproduction in prf mice, and suggest that perforin normally functions to down modulate antigen presentation. Multiple cell types that express perforin are known to interact with DC's. In order to identify which of these populations would normally down modulate stimulation by DC's, we have performed a series of cell depletion, transfer, and bone marrow transplantation experiments. These studies have revealed that perforin-expressing cell types can influence both DC function and in vivo IFN-g production, and suggest that CD8+ T cells are the most critical cell type exerting this regulatory effect. Based on our preliminary studies, we hypothesize that perforin-dependant cytotoxic killing of selected dendritic cells by CD8+ T cells limits the entry and/or persistence of antigen in DC populations, and thereby limits immune activation.To test our hypothesis, we will pursue the following specific aims: Aim 1.) Define how antigen handling and presentation differ between WT and prf DC subsets after LCMV infection. Aim 2.) Determine whether CD8+ T cells are the principle cell type that suppresses DC stimulatory function via a perforin-dependant mechanism. This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders.