Macrophage Polarization and Function in GVHD - PROJECT SUMMARY / ABSTRACT Graft versus host disease (GVHD) remains the major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and occurs following activation and expansion of alloreactive T cells. Among the tissues and organs impacted by GVHD, the gastrointestinal (GI) tract is a critical and frequently involved locus of disease. Clinically, GVHD damages the gastrointestinal (GI) tract in up to 60% of transplant patients, and the presence of GI GVHD often exacerbates GVHD in other target organs. Improved strategies to eliminate GVHD or decrease its severity are needed. Within the GI tract, macrophages are a tissue-resident innate immune cell population that are derived from donor monocytes and possess plasticity between proinflammatory and anti- inflammatory phenotypes. Macrophage survival and proliferation is largely regulated by signaling through the colony stimulating factor 1 receptor (CSF-1R), of which M-CSF and interleukin-34 (IL-34) are the known ligands. In preliminary data, we have shown that the absence of host IL-34 results in significantly impaired GI epithelial barriers and exacerbated GVHD lethality. Mechanistically, the absence of host IL-34 led to skewing of donor macrophages towards an inflammatory phenotype. Our lab further identified that the protection conferred by IL-34 was contingent on apolipoprotein E (ApoE) production by donor macrophages. Based on these preliminary findings, I hypothesize that IL-34 functions as a cytokine rheostat that skews macrophage polarization towards an anti-inflammatory phenotype and thereby prevents pathological damage within the GI tract during GVHD. In this proposal, I have outlined an approach to define the regulation of IL-34 production in intestinal epithelial cells in GI GVHD, delineate mechanisms by which IL-34 inhibits the emergence of proinflammatory T cells within the colon in GVHD, and define the role of ApoE in IL-34 mediated regulation of GI GVHD. I am firmly committed to an independent academic research career and am strongly supported in my career development and research goals by my mentor, advisors, and the Department of Pediatrics at the Medical College of Wisconsin (MCW). Institutional support includes 75% protected time for research, dedicated wet-lab bench space, independent office space, and start-up funding for equipment and supplies. Under the guidance of my primary mentor, William Drobyski, MD, and advisors Xue-Zhong Yu, MD, MS, MBA, Chien-Wei Lin, PhD, Bonnie Dittel, PhD, and Joy Lincoln, PhD, I will advance my skills in cutting-edge single cell analytics techniques and applied bioinformatics with direct application to the specific aims of this proposal. Completion of my comprehensive training plan will provide me with the skills and experience necessary to become a successful independent investigator with expertise in a novel IL-34, macrophage, and T cell signaling axis that influences allogeneic immune responses in the GI tract during GVHD.
