Thursday, November 21, 2024
11/21/2024
Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). During the acute phase of this disease, a restricted set of organs is affected of which the gastrointestinal (GI) tract is the most clinically significant. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part, by activating donor innate and T cell populations which subsequently induce tissue damage. We previously demonstrated that CD4+ T cell production of granulocyte- macrophage colony stimulating factor (GM-CSF) plays a critical inflammatory role in the pathophysiology of GI GVHD. More recently, we have identified two CD4+ GM-CSF+ T cell populations within the GVHD colon microenvironment that possess distinct transcriptional profiles, employ non-overlapping gene regulatory units, emerge with divergent temporal kinetics, have differential responsiveness to IL-7, and are distinguishable by the presence or absence of IFN-γ co-expression, suggesting that they may have different pathogenic roles in mediating GVHD in the GI tract. In addition, our preliminary studies have uncovered a previously unappreciated interleukin 34 (IL-34)-mediated regulatory pathway that inhibits the emergence of CD4+ GM-CSF+ T cells in the GI tract, indicating the existence of a potential therapeutically targetable cytokine to reduce GM-CSF- mediated inflammation in this tissue site. The overall goal of this proposal is therefore to delineate mechanistic pathways by which CD4+ GM-CSF+ T cells promote pathological damage in the GI tract and define how these populations are regulated by IL-34. Our overall hypothesis is that there exist discrete CD4+ GM- CSF+ T cell populations that have distinct functional roles in mediating pathological damage in the GI tract and that are regulated by the host production of IL-34. Studies in Specific Aim 1 will define the pathogenicity of CD4+ GM-CSF+ T cell populations during GVHD. To address this question, we will employ a recently created GM-CSF fate reporter mouse model that faithfully identifies viable GM-CSF- expressing CD4+ T cells in GVHD target organs. Experiments in Specific Aim 2 will identify key transcription factors and define the role of IL-7 in the development of CD4+ GM-CSF+ T cells. We will employ genetically modified murine models that will ascertain the extent to which specific transcription factors are required for the development and pathogenicity of CD4+ GM-CSF+ T cells and determine the dependency of these cells on IL-7 receptor signaling. Studies in Specific Aim 3 will characterize how IL-34 regulates GM-CSF-responsive innate immune cell populations in the GI tract during GVHD and affects the emergence of CD4+ GM-CSF+ T cells. Experiments will identify mechanistic pathways by which IL-34 regulates GVHD and determine whether these pathways can be therapeutically targeted to reduce disease severity. The overall objective of this proposal is to develop new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic HSCT recipients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
