Tuesday, April 30, 2024
4/30/2024
Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for patients with hematological malignancies (i.e. leukemia and lymphoma), through graft versus leukemia/lymphoma (GVL) effect mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) caused by the same alloreactive T cells remains a major obstacle. Chronic GVHD (cGVHD), a systemic autoimmune-like syndrome, remains a major cause of morbidity and mortality in long-term survivors of Allo-HCT. During the past decade, we have used murine and humanized murine models of cGVHD and biospecimens from cGVHD patients to demonstrate that CD4+ T cells and B cells and their interactions in GVHD target tissues such as the liver, lung and skin play a critical role in the pathogenesis and persistence of the disease. The premise of this new proposal is that deeper mechanistic understanding of the interactions between non-circulating tissue- resident CD4+ memory T (Trm) and tissue-resident B (Brm) cells in GVHD target tissues will identify new therapeutic targets for prevention or treatment of cGVHD. In Aim 1, we will determine whether CD4+ Trm cells initiate formation of tertiary lymphoid structures (TLS) in GVHD target tissues, in which Ly108+ stem cell-like progenitors maintain the pool of Trm and Brm to perpetuate cGVHD pathogenesis. We will also develop novel cell-penetrating PS-Cas9-gRNA to target STAT3 in donor T cells to prevent development of pathogenic CD4+ Trm and cGVHD while preserving GVL activity, because our recent studies indicate that STAT3 is required for Trm development. In Aim 2, we will determine whether B cell helper PD-1hiPSGL1loCD4+ Trh cells interact with T-bet+ Brm cells to produce autoantibodies that augment systemic tissue damage. In Aim 3, we will determine whether non-B cell helper PSGL1hiCD4+ Trm cells interact with dendritic cells, macrophages, and fibroblasts in cGVHD target tissues to mediate damage and fibrosis in an IL-33/ST2 pathway-dependent manner. These studies have high biological and translational significance and may lead to a paradigm shift in our understanding of cGVHD pathogenesis and to development of novel approaches for preventing and treating cGVHD.
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).
