Monocytes and the Intestinal Microbiota following ALLO-HSCT

$305,385P01FY2015CANIH

Sloan-Kettering Inst Can Research, New York NY

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Abstract

Monocytes provide defense against infection and serve as progenitors for tissue macrophages and dendritic cells. Recruitment of monocytes to sites of infection begins with trafflcl<ing from the bone marrow into the bloodstream, a process that is driven by CCL2 expression by bone man-ow mesenchymal stem cells (MSCs). Circulating microbial ligands stimulate Toll-like receptor (TLRs) on MSCs, inducing CCL2 expression. Inflammatory monocytes play an important role in immune reconstitution and antimicrobial defense following allo-HSCT. We hypothesize that the intestinal microbiota and the integrity ofthe intestinal epithelial barrier influence monocyte frequencies and trafficking. Our goal is to characterize monocyte reconstitution and determine the contributions ofthe intestinal microbiota and the development of GvHD on monocyte trafficking and differentiation, with the goal of optimizing immune reconstitution and antimicrobial defense. Our first aim is to investigate Ly6Chi monocyte reconstitution and the localization and responsiveness of monocytes and MSCs following allo-HSCT. We will use CCR2 and MCP-1 reporter mice to investigate monocytes following allo-HSCT. We will use a conditional MCP-1 knockout mouse strain to determine the contribution of MSCs to the development ofthe inflammatory monocyte compartment. Our second aim is to determine the Impact of GvHD on monocyte trafficking and to determine the role of Ly6Chi monocytes in the development of GvHD. We will aiso quantify inflammatory monocyte numbers in patients following allo-HSCT and correlate circulating monocyte levels with subsequent development of GvHD. Our third aim addresses our hypothesis that changes in the intestinal microbota following allo-HSCT influence monocyte emigration from bone marrow. We will investigate changes in the intestinal microbiota during allo- HSCT using high-throughput 16S rDNA sequencing and correlate changes in the intestinal microbiota with circulating inflammatory monocyte levels and activation. The studies described in this project will identify in vivo mechanisms that drive reconstitution ofthe monocyte compartment and will define the role of the intestinal microbiota in re-establishing immune homeostasis following allo-HSCT.

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