INFLAMMATORY MONOCYTES IN ALLO-HSCT

循环中的单核细胞分化为组织巨噬细胞和树突状细胞，提供免疫 对微生物病原体的防御。血流中的单核细胞由不同的亚群组成 分化潜力和贩运模式。循环单核细胞亚群的重建各不相同 异基因造血干细胞移植后患者与我们假设 这对感染的易感性有影响。我们研究的目标是描述 不同单核细胞亚群在小鼠抵抗烟曲霉感染中的作用 异基因造血干细胞移植后真菌感染模型与IP人类 HSCT)。我们的第一个目标是研究异基因移植后小鼠的循环和组织炎症单核细胞的特征。 HSCT。单核细胞趋化蛋白-1在CCR2介导的组织单核细胞再增殖中的作用将被研究 移植后，将确定移植物抗宿主病对这一过程的影响。我们将确定 移植小鼠对烟曲霉肺部感染的易感性及其相关性 易感性与炎性单核细胞的存在和激活状态有关。我们的第二个目标是 炎性单核细胞介导对侵袭性真菌感染的保护能力 Allo-HSCT设置。我们将在体外从骨髓前体细胞产生小鼠单核细胞亚群 调查它们对烟曲霉菌感染的中介保护能力。重组 将给移植的小鼠注射趋化因子和生长因子以加速和增强 单核细胞重建。天然免疫受体介导的信号转导对单核细胞介导的影响 同种异体移植环境中的抗真菌防御将被调查。我们的第三个目标是前瞻性地 研究allo-HSCT受者的单核细胞亚群频率和功能，并将其与 真菌感染的发展。此外，我们还将研究骨髓和外周血干细胞 存在单核细胞亚群的同种异体移植。单核细胞将从移植物和异基因造血干细胞移植中分离出来 将对患者及其灭活烟曲霉分生孢子和菌丝的能力进行调查。相关性： 这些研究的结果可能为未来的临床方案提供基础，以研究输注 异基因干细胞移植患者分化的单核细胞增强对真菌的抵抗力 病原体..

Circulating monocytes differentiate into tissue macrophages and dendritic cells that provide immune defense against microbial pathogens. Monocytes in the bloodstream consist of subpopulations with distinct differentiation potentials and trafficking patterns. Reconstitution of circulating monocyte subsets varies between patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and we postulate that this has implications for susceptibility to infection. The goal of our studies is to characterize the contribution of distinct monocyte subsets to defense against Aspergillus fumigatus infection in a murine model of fungal infection and ip humans following allogeneic hematopoietic stem cell transplantation (allo- HSCT). Our first aim is to characterize circulating and tissue inflammatory monocytes in mice following allo- HSCT. The contribution of MCP-1to CCR2-mediated monocyte repopulation of tissues will be investigated following transplantation and the impact of GVHD on this process will be determined. We will determine the susceptibility of transplanted mice to pulmonary infection with Aspergillus fumigatus and correlate susceptibility with the presence and activation status of inflammatory monocytes. Our second aim is to characterize the ability of inflammatory monocytes to mediate protection against invasive fungal infection in the allo-HSCT setting. We will generate murine monocyte subsets in vitro from bone marrow precursors and investigate their ability to mediate protection against Aspergillus fumigatus infections. Recombinant chemokines and growth factors will be administered to transplanted mice to accelerate and enhance monocyte reconstitution. The impact of innate immune receptor mediated signaling on monocyte mediated antifungal defense in the allo-transplant setting will be investigated. Our third aim is to prospectively investigate monocyte subset frequencies and function in allo-HSCT recipients and correlate these with development of fungal infections. In addition, we will investigate bone marrow and peripheral blood stem cell allografts for the presence of monocyte subsets. Monocyteswill be isolated from grafts and from allo-HSCT patients and their ability to inactivate A. fumigatus conidia and hyphae will be investigated. Relevance: The results of these studies may provide a foundation for future clinical protocols to investigate the infusion of differentiated monocytes into allogeneic stem cell transplant patients to enhance resistance to fungal pathogens..