Allogeneic hematopoietic stem cell transplantation (HSCT) is a therapeutic procedure that is used to treat advanced hematologic malignancies or other blood disorders. HSCT involves the administration of chemotherapy and/or radiation to patients, followed by the transplant of hematopoietic stem cells from a sibling or unrelated matched donor. Because transplant recipients are """"""""rescued"""""""" from the bone marrow suppressing effects of the pre-transplant conditioning regimen by the subsequent infusion of healthy stem cells, very high doses of chemotherapy can be administered in an effort to overcome any drug resistance displayed by the malignancy. In addition, mature donor cells present in the stem cell product can mount potent immune responses against any residual cancer that might still be present. Unfortunately, however, these immune reactions are not specific for diseased cells, and normal host tissues can be damaged as well. This process is referred to as graft-versus-host disease (GVHD), and can result in a severe skin rash, profound diarrhea, or liver injury. GVHD is most often treated with high doses of steroids, a therapy that is not always effective and associated with substantial side effects. As a result, laboratories are actively exploring new approaches for treating this difficult disorder. Recently Dr. Coghill, the principal investigatorof the present proposal, published animal model data showing that donor cells lacking the lymph node trafficking receptor CC-Chemokine receptor 7 (CCR7) generate greatly attenuated GVHD responses when transplanted into recipient mice. Cells without CCR7 failed to traffic normally to recipient lymph nodes, and demonstrated a reduced capacity to expand within the spleen. Importantly, however, donor cells lacking CCR7 were able to mount potent anti-cancer immune effects after transplant, and donor regulatory T cells (a population of anti-inflammatory cells) were able to prevent GVHD in the absence of CCR7. Collectively, these findings indicated that blocking the function of CCR7 might prove to be a new and effective approach for preventing GVHD without inhibiting beneficial anti-cancer effects or interfering with the ability of donor regulatory T cells to down-regulate overly aggressive immune responses. There are currently no drugs that block the function of CCR7 that are available for use in HSCT patients or for study in animal models. As a result, this proposal describes a strategy for developing antagonists against CCR7. For this work, we will use genetically engineered cell lines which generate a color signal in the presence of the natural ligands for CCR7: CCL19 and CCL21. With these cells, we will robotically screen a collection of approximately 120,000 small molecules for agents with CCR7 antagonist properties, looking for compounds that are able to block color generation in our primary reporter assay. Actives from the primary screen would then be assessed for cellular toxicity and for specificity against CCR7. Lead compounds would next be evaluated for functionality by assessing their ability to impair chemotaxis (cellular movement) in vitro, a process that is mediated by CCR7. Ultimately, promising compounds would be evaluated for efficacy in vivo by examining their capacity to inhibit GVHD in mouse transplant models. While beyond the scope of the present proposal, lead compounds could be continually refined using medicinal chemistry approaches to maximize their potency and selectivity against CCR7, and developed into drugs for use in human patients undergoing stem cell transplantation. In addition to this CCR7 antagonist discovery effort, mechanistic studies are described to better understand how donor regulatory T cells function after HSCT without CCR7, as previous studies had suggested a critical role for this receptor in their normal function. This proposal is being submitted for a K08 mentored career development award. As a result, the project is designed to provide a substantial educational component for the principal investigator in addition to accomplishing its specific scientific objectives. Dr. Coghill's long-trm goal is to run his own laboratory, with a focus on GVHD pathogenesis and the use of novel, small molecule therapeutics for its treatment and/or prevention. While possessing a strong background in hematology and oncology, this work will offer Dr. Coghill an opportunity to receive additional in-depth instruction in immunology, cell signaling, and the early phases of drug discovery. Dr. Coghill will learn first-hand from an expert mentoring team led by Drs. Jonathan Serody and Stephen Frye, world experts in the fields of lymphocyte trafficking and drug development respectively. A formalized didactic curriculum is also proposed, including coursework in pharmacology, cell biology, grantsmanship, and the responsible conduct of research. Through these experiences, Dr. Coghill will obtain the skills necessary to transition to an independent, NIH funded laboratory investigator.
Allogeneic hematopoietic stem cell transplantation is a therapeutic modality that is used to treat advanced blood related cancers or other hematologic disorders. Its effectiveness is greatly limited, however, by graft-versus-host disease (GVHD), a process by which donor immune cells attack normal recipient tissues. This proposal details the early development phases of a candidate drug directed against the lymph node homing receptor CC-Chemokine receptor 7 (CCR7) that might ultimately be used to prevent GVHD in human stem cell transplant patients.
|Fowler, Kenneth A; Jania, Corey M; Tilley, Stephen L et al. (2017) Targeting the Canonical Nuclear Factor-?B Pathway with a High-Potency IKK2 Inhibitor Improves Outcomes in a Mouse Model of Idiopathic Pneumonia Syndrome. Biol Blood Marrow Transplant 23:569-580|
|Coghill, James M; Fowler, Kenneth A; West, Michelle L et al. (2013) CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease. Blood 122:825-36|