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

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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.