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，我们试图通过检查CCR2+炎性单核细胞和CCR2+单核细胞衍生的树突状细胞（mo - dc）在ABMT与无GVHD的背景下防御真菌感染的具体贡献来进一步了解ABMT。在初步研究中，我们采用了一种新的小鼠品系，该品系允许选择性地消耗CCR2+单核细胞，以揭示CCR2+炎性单核细胞在防御IA中的先前未被识别的重要作用。基于我们已发表和未发表的观察结果，我们提出的研究将验证两个主要假设：1)由于CCR2+单核细胞重构和/或功能受损，ABMT导致对IA的易感性增强；2)由于保护性真菌特异性CD4 T细胞活化受损，ABMT和GVHD导致对IA的易感性增强

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+ inflammatory monocytes and CCR2+ monocyte-derived dendritic cells (Mo-DCs) in defense against fungal infection in the context of ABMT with our without GVHD. In preliminary studies we have employed a novel mouse strain that allows for the selective depletion of CCR2+monocytes to uncover a previously unidentified essential role for CCR2+inflmmatory monocytes in defense against IA. Based on our published and unpublished observations the proposed studies will test two main hypothesis: 1) ABMT leads to enhanced susceptibility to IA due to impairments in CCR2+monocyte reconstitution and/or function 2) ABMT and GVHD lead to enhanced susceptibility to IA due to impairments in the activation of protective fungus- specific CD4 T cell responses. The proposed studies will be made possible by employing novel mouse strains that facilitate the selective tracking and depletion of CCR2+ inflammatory 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 identify crucial factors that control susceptibility to fungal infection. Moreover, we believe that our studies will uncover novel mechanisms of susceptibility in the context of ABMT and lay the foundation for future translational studies to exploit inflammatory monocytes in the prevention of life-threatening fungal infections in ABMT patients.