Monocytic-MDSCs as resolution mediators of post-transplant lung ischemia-reperfusion injury

项目总结 肺移植后缺血再灌注损伤是一种不可避免的损害，发生在移植后早期。 在其他健康的移植物中，可能会导致严重的功能障碍。这种损伤的特点是有一种粗壮的 炎症反应如果得不到解决，最终会导致短期和长期的死亡 阻碍了肺移植的成功率。促进炎症消退的机制， 尤其是这一无菌侮辱的解决方案，没有很好的特点，因此代表了一种有吸引力的 可能发现治疗靶点的研究机会。最近，移植研究的重点是 抑制免疫反应的固有细胞的治疗潜力，称为髓源性抑制因子 细胞(MDSCs)。这是一个异质性的细胞群体，由粒细胞样细胞(G-MDSC)和 单核细胞样细胞(M-MDSCs)未成熟的髓系细胞，具有强大的免疫抑制特性。他们的角色是 主要的免疫抑制调节剂在癌症环境中已被广泛阐明，其发现 在移植中可翻译，但不被确认。提议的F31 NRSA应用程序将使用试验性的 肺IRI模型，小鼠原位肺移植模型，以及检验总体假设的体外方法 M-MDSC亚群有助于肺移植后缺血再灌注损伤的修复。在目标1中，我 将验证M-MDSC促进实验性肝门结扎诱导的肺IRI消退的假设 肺损伤模型通过调节特异性免疫细胞的激活来实现。在目标2中，我将测试假设 M-MDSCs在小鼠原位肺移植中以免疫抑制的方式减轻肺损伤 模特。这个项目将揭示M-MDSCs在肺中的行为，这对理解 它们作为一种诱导移植耐受的细胞疗法的全部潜力。

PROJECT SUMMARY Post-lung transplant ischemia reperfusion injury is an unavoidable insult that occurs early in the post-transplant period and can cause significant dysfunction in an otherwise healthy graft. This injury is characterized by a robust inflammatory response that when unresolved, can lead to both short- and long-term mortality, ultimately hindering success rates of lung transplantation. The mechanisms that facilitate the resolution of inflammation, and specifically the resolution of this sterile insult, are not well characterized, and thus represent an attractive research opportunity that could uncover therapeutic targets. Recently, transplant research has focused on the therapeutic potential of innate cells that suppress immune response, referred to as Myeloid-Derived Suppressor Cells (MDSCs). This is a heterogeneous population of cells made up of granulocytic-like (G-MDSC) and monocytic-like (M-MDSCs) immature myeloid cells with potent immunosuppressive properties. Their role as master immunosuppressive regulators has been extensively elucidated in cancer settings, with findings translatable, but not confirmed, in transplantation. The proposed F31 NRSA application will use an experimental lung IRI model, a murine orthotopic lung transplant model, and in vitro methods to test the overall hypothesis that the M-MDSC subset facilitates the resolution of post-lung transplant ischemia reperfusion injury. In Aim 1, I will test the hypothesis that M-MDSC facilitate the resolution of lung IRI in an experimental hilar-ligation induced lung injury model through modulation of specific immune cell activation. In Aim 2, I will test the hypothesis that M-MDSCs act in an immunosuppressive manner to reduce lung injury in a murine orthotopic lung transplant model. This project will reveal insights into the actions of M-MDSCs in the lung which is crucial to understanding their full potential as a cellular therapy in the induction of graft tolerance.