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

点击翻译按钮获取中文摘要

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 Based on our published and unpublished observations the proposed studies will test two main hypothesis: 1) ABMT leads to enhanced susceptibility to IA due to impairments in CCR2+monocyte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.