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

描述（由申请人提供）：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包括高水平的炎症细胞因子、多系统器官功能衰竭、凝血功能障碍和噬血细胞症的发展。它与另一种遗传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）有相似的外观。然而，与fHLH不同的是，MAS患者没有与该疾病相关的基因突变。因此，MAS与fHLH的初始事件可能不同。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基因操作或感染的情况下产生MAS样疾病的模型。该模型提供了MAS患者倾向于炎症toll样受体（TLR）激活状态升高的观察之间的第一个联系。通过重复使用TLR9刺激，小鼠产生mas样综合征。与fHLH一样，该疾病是由干扰素γ (IFNγ)介导的。与fHLH不同的是，这种IFNγ在很大程度上是在骨髓细胞中产生的，这再次证明了MAS和fHLH之间的差异以及对独特模型的需求。该模型也证明了白细胞介素-10 （IL-10）在防止MAS和噬血细胞症发展中的关键作用。本研究旨在利用互补的遗传和药理学技术，鉴定细胞对IFNγ的反应，这些反应的性质，以及MAS中保护性IL-10的来源。骨髓嵌合体将用于在特定细胞群上产生缺乏IFNγ受体的小鼠，以确定应答细胞。过继性转移技术将用于确定产生保护性IL-10反应的重要细胞类型。重组细胞因子将用于研究细胞因子暴露与TLR刺激之间的时间关系。这些研究产生的数据将为合理靶向IFNγ和IL-10及其在治疗MAS中的相关细胞反应提供基础。这将标志着在开发MAS特异性疗法方面向前迈出了重要的一步，而不是不适当地借鉴fHLH方案的护理标准。

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.