Role of CCR2+ monocytes and Mo-DCs in defense against IA and GVHD development

描述（由申请人提供）：同种异体骨髓移植（ABMT）可以作为治疗多种血液恶性肿瘤的救命手段。ABMT的广泛应用受到严重并发症的阻碍，包括危及生命的真菌感染（特别是侵袭性曲霉病，IA）和移植物抗宿主病（GVHD）的发展。ABMT的治疗效果可以通过新的治疗干预措施来改善感染和GVHD的副作用，从而得到更广泛的利用。对ABMT基本生物学方面的详细了解将有助于确定开发创新疗法的相关靶点。在这个应用中，我们通过检查CCR2+单核细胞和单核细胞衍生的树突状细胞（mo - dc）在抵抗真菌感染和GVHD发展中的具体贡献，寻求进一步我们目前对ABMT的了解。在提出的研究中，我们将验证两个主要假设：1)单核细胞通过直接抗真菌作用和在维持ABMT后T细胞反应中发挥非重复作用来阻止ABMT后IA的发展；2)Mo-DC作为供体和/或宿主来源的dc影响GVHD的发展。通过采用新的小鼠品系，促进CCR2+单核细胞和mo - dc的选择性跟踪和消耗，拟议的研究将成为可能。我们还将利用我们之前开发的模型来跟踪真菌特异性CD4 T细胞反应的体内发展，以专门研究ABMT和GVHD对抗真菌免疫发展的影响。总之，这些研究的成功完成将极大地促进我们对ABMT后免疫重建的理解，并阐明以前未知的GVHD发展方面。此外，我们相信我们的研究有可能揭示CCR2+单核细胞和衍生细胞的新贡献，这些细胞可以用来预防ABMT后危及生命的真菌感染和GVHD的发展。

DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (ABMT) can be a life-saving procedure as therapy against a variety of hematologic malignancies. The broad application of ABMT has been hampered by serious complications including life-threatening fungal infections (especially invasive aspergillosis, IA) and graft versus host disease (GVHD) development. The curative effects of ABMT could be more broadly exploited by ameliorating infection and GVHD side effects through novel therapeutic interventions. A detailed understanding of basic biological aspects of ABMT would facilitate the identification of relevant targets for the development of innovative therapies. In this application we seek to further our current knowledge of ABMT by examining the specific contributions of CCR2+ monocytes and monocyte-derived dendritic cells (Mo-DCs) in defense against fungal infection and in the development of GVHD. In the proposed studies we will test two main hypothesis: 1) monocytes prevent the development of IA after ABMT through direct antifungal effects and by playing non- redundant roles in maintaining T cell responses after ABMT, 2) Mo-DC influence the development of GVHD as donor and/or host derived DCs. The proposed studies will be made possible by employing novel mouse strains that facilitate the selective tracking and depletion of CCR2+ monocytes and Mo-DCs. We will also exploit our previously developed model for tracking the in vivo development of fungus-specific CD4 T cell responses to specifically examine the impact of ABMT and GVHD on the development of antifungal immunity. Altogether, the successful completion of the proposed studies would significantly advance our understanding of immune reconstitution after ABMT and illuminate previously unknown aspects of GVHD development. Moreover, we believe that our studies have the potential to uncover novel contributions of CCR2+ monocytes and derivate cells that could be exploited to prevent life-threatening fungal infections and GVHD development after ABMT.