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一种危及生命的并发症。 MAS 包括高水平的炎症细胞因子、多系统器官衰竭、凝血病和噬血细胞的发生。它与另一种遗传性细胞因子风暴综合征——家族性噬血细胞性淋巴组织细胞增多症（fHLH）具有相似的外观。然而，与 fHLH 不同的是，MAS 患者不具有与该疾病相关的基因突变。据此，MAS 中导致疾病的初始事件可能与 fHLH 中不同。我们最近开发了一种新型 MAS 小鼠模型，这是第一个无需基因操作或感染即可产生类似 MAS 疾病的模型。该模型提供了 MAS 患者倾向于高度炎症 Toll 样受体 (TLR) 激活状态的观察结果之间的第一个联系。通过重复刺激 TLR9，小鼠会出现类似 MAS 的综合征。与 fHLH 一样，该疾病是由干扰素-γ (IFNγ) 介导的。与 fHLH 不同，这种 IFNγ 大部分是在骨髓细胞中产生的，再次证明了 MAS 和 fHLH 之间的差异以及对独特模型的需求。该模型还证明了白介素 10 (IL-10) 在防止 MAS 和噬血细胞发生方面的关键作用。该提案旨在利用互补的遗传和药理学技术来确定对 IFNγ 的细胞反应者、这些反应的性质以及 MAS 中保护性 IL-10 的来源。骨髓嵌合体将用于产生特定细胞群上缺乏 IFNγ 受体的小鼠，以确定响应细胞。过继转移技术将用于确定对产生保护性 IL-10 反应重要的细胞类型。将施用重组细胞因子来研究细胞因子暴露和 TLR 刺激之间的时间关系。这些研究产生的数据将为 IFNγ 和 IL-10 的合理靶向及其在治疗 MAS 中的相关细胞反应提供基础。这将标志着开发 MAS 特定疗法向前迈出的重要一步，而不是不适当地借用 fHLH 协议的护理标准。

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.