Circulating monocytes differentiate into tissue macrophages and dendritic cells that provide immunedefense against microbial pathogens. Monocytes in the bloodstream consist of subpopulations with distinctdifferentiation potentials and trafficking patterns. Reconstitution of circulating monocyte subsets variesbetween patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and we postulatethat this has implications for susceptibility to infection. The goal of our studies is to characterize thecontribution of distinct monocyte subsets to defense against Aspergillus fumigatus infection in a murinemodel of fungal infection and ip humans following allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Our first aim i s to characterize circulating and tissue inflammatory monocytes in mice following allo-HSCT. The contribution of MCP-1to CCR2-mediated monocyte repopulation of tissues will be investigatedfollowing transplantation and the impact of GVHD on this process will be determined. We will determine thesusceptibility of transplanted mice to pulmonary infection with Aspergillus fumigatus and correlatesusceptibility with the presence and activation status of inflammatory monocytes.
Our second aim i s tocharacterize the ability of inflammatory monocytes to mediate protection against invasive fungal infection inthe allo-HSCT setting. We will generate murine monocyte subsets in vitro from bone marrow precursors andinvestigate their ability to mediate protection against Aspergillus fumigatus infections. Recombinantchemokines and growth factors will be administered to transplanted mice to accelerate and enhancemonocyte reconstitution. The impact of innate immune receptor mediated signaling on monocyte mediatedantifungal defense in the allo-transplant setting will be investigated.
Our third aim i s to prospectivelyinvestigate monocyte subset frequencies and function in allo-HSCT recipients and correlate these withdevelopment of fungal infections. In addition, we will investigate bone marrow and peripheral blood stem cellallografts for the presence of monocyte subsets. Monocyteswill be isolated from grafts and from allo-HSCTpatients and their ability to inactivate A. fumigatus conidia and hyphae will be investigated. Relevance: Theresults of these studies may provide a foundation for future clinical protocols to investigate the infusion ofdifferentiated monocytes into allogeneic stem cell transplant patients to enhance resistance to fungalpathogens..

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Sloan-Kettering Institute for Cancer Research
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