The Opposing Roles of IL-10 and IFN-gamma in Macrophage Activation Syndrome

描述(申请人提供)：巨噬细胞激活综合征(MAS)是许多儿科风湿病的危及生命的并发症。MAS包括高水平的炎性细胞因子、多系统器官衰竭、凝血障碍和吞噬血细胞的发展。它与另一种遗传性细胞因子风暴综合征--家族性噬血细胞淋巴组织细胞增多症(FHLH)相似。然而，与fHLH不同的是，MAS患者没有与这种疾病相关的基因突变。根据这一观点，在MAS中导致疾病的初始事件可能与在fHLH中不同。我们最近开发了一种新的MAS小鼠模型，这是第一个在不需要遗传操作或感染的情况下产生MAS样疾病的模型。这个模型提供了MAS患者倾向于炎性Toll样受体(TLR)激活状态增强的观察结果之间的第一个联系。通过重复使用TLR9刺激，小鼠会出现类似MAS的综合征。和FHLH一样，这种疾病是由干扰素-γ(干扰素γ)介导的。与FHLH型不同，这种干扰素γ大部分是在髓系细胞中制造的，再次证明了MAS和FHLH型之间的差异以及对独特模型的需要。该模型还证明了白介素10(IL-10)在防止MAS和吞噬血细胞的发展中的关键作用。这项建议寻求确定干扰素γ的细胞反应者，这些反应的性质，以及使用互补的遗传和药理学技术在大脑中动脉粥样硬化中保护性IL-10的来源。骨髓嵌合体将被用来产生特定细胞群体上缺乏干扰素γ受体的小鼠，以确定反应细胞。过继转移技术将被用来确定对产生保护性IL-10反应重要的细胞类型。重组细胞因子将被用来研究细胞因子暴露和TLR刺激之间的时间关系。这些研究的数据将为合理靶向干扰素γ和IL-10，以及它们在治疗多发性硬化时的相关细胞反应提供基础。这将标志着在开发MAS特定疗法方面向前迈出了重要的一步，而不是不适当地从fHLH方案中借用的护理标准。

DESCRIPTION (provided by applicant): Macrophage Activation Syndrome (MAS) is a life threatening complication of many pediatric rheumatology diseases. MAS consist of high levels of inflammatory cytokines, multi-system organ failure, coagulopathy, and the development of hemophagocytosis. It bears a similar appearance to another genetic cytokine storm syndrome, Familial Hemophagocytic Lymphohistiocytosis (fHLH). However, unlike fHLH, patients with MAS do not have genetic mutations associated with the disease. According, the initial events leading to the disease are likely different in MAS than in fHLH. We have recently developed a novel mouse model of MAS, the first model to produce an MAS-like disease without the need for genetic manipulations or infections. This model provides the first link between the observations that patients with MAS tend to heightened states of inflammatory Toll-like receptor (TLR) activation. By using repeated TLR9 stimulation, mice develop an MAS-like syndrome. Like fHLH, the disease is mediated by Interferon-gamma (IFNγ). Unlike fHLH, this IFNγ is made in large part myeloid cells, again demonstrating the difference between MAS and fHLH and the need for unique models. This model has also demonstrated a critical role for Interleukin-10 (IL-10) in protecting against the development of MAS and hemophagocytosis. This proposal seeks to identify the cellular responders to IFNγ, the nature of these responses, and the source of protective IL-10 in MAS using complementary genetic and pharmacologic techniques. Bone marrow chimera will be used to generate mice lacking the receptors for IFNγ on specific cellular populations to determine the responding cells. Adoptive transfer techniques will be used to determine the cell type important for making the protective IL-10 response. Recombinant cytokines will be administered to investigate the temporal relationship between cytokine exposure and TLR stimulus. The data generated from these studies will provide a basis for rational targeting of IFNγ and IL-10, and their associated cellular responses in treating MAS. This will mark an important step forward in developing MAS specific therapies as opposed to the standard of care of borrowing inappropriately from the fHLH protocols.