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

描述(申请人提供)：异基因骨髓移植(ABMT)可以是一种挽救生命的程序，作为治疗各种血液系统恶性肿瘤的方法。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(尤其是侵袭性曲霉病)和移植物抗宿主病(GVHD)的发展。通过新的治疗干预措施改善感染和GVHD副作用，可以更广泛地发挥ABMT的疗效。对ABMT的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目标。在这一应用中，我们试图通过检测CCR2+单核细胞和单核细胞来源的树突状细胞(Mo-DC)在抵御真菌感染和GVHD发生中的特殊作用来进一步了解ABMT。在拟议的研究中，我们将检验两个主要假设：1)单核细胞通过直接抗真菌作用和在维持ABMT后T细胞反应中发挥非多余作用来预防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。建议的研究将通过使用新的小鼠品系来实现，这些品系有助于选择性跟踪和耗尽CCR2+单核细胞和Mo-DC。我们还将利用我们先前开发的模型来跟踪真菌特异性CD4T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，拟议研究的成功完成将大大促进我们对ABMT后免疫重建的理解，并阐明GVHD发生之前未知的方面。此外，我们相信，我们的研究有可能发现CCR2+单核细胞和衍生细胞的新贡献，可用于预防ABMT后危及生命的真菌感染和GVHD的发生。

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.