Intestinal epithelial cell (IEC) damage by the donor alloreactive T cells causes gastrointestinal (GI) graft-versus-host disease (GVHD) allogeneic bone marrow transplantation (BMT). The host IEC intrinsic mechanisms that enhance their resistance to the damage by the donor alloreactive T cells might have therapeutic potential in GVHD. IEC homeostasis and resistance depends on complex interactions between the metabolic energy substrates and the regulation of transcription and epigenetic chromatin modifications such as histone acetylation. But the mechanisms of IEC resistance and the relevance of metabolic regulation of histone acetylation in reducing the severity of GVHD has heretofore not been studied. In the current cycle, we have demonstrated and published that epigenetic regulation by systemic administration of histone deacetylase inhibitors (HDACi) regulates experimental GVHD and successfully translated it into a proof of concept human trial for prevention of clinical GVHD. Preliminary data generated during this cycle also demonstrate a significant alteration in the IEC energy substrates that are derived from microbial metabolites, specifically the essential short chain fatty acids (SCFA), such as butyrate in the intestinal tissues after allogeneic BMT. Preliminary data also show that butyrate, which is a known HDACi, enhances histone acetylation, modulates IECs sensitivity damage, and regulates GVHD in vivo. But the pathways of sensing and the mechanisms underlying the butyrate-mediated effects are not known. Therefore, in this proposal, we will build on these exciting and novel preliminary observations to explore the interplay between microbial metabolite and the HDAC inhibitor, butyrate, and its effects on epigenomic alterations of the IECs in reducing GI GVHD. Specifically, we will test the central premise that endogenous intestinal microbial metabolite, butyrate, promotes acetylation of intestinal IECs and negatively regulates GI GVHD. We will explore this premise in the following three specific aims: 1. To determine the pathways of sensing microbial metabolite butyrate by the intestinal epithelial cells (IECs) and its impact on GVHD. In this SA we will test the hypothesis that chemo- sensing of the microbial metabolite butyrate by the G-protein coupled receptor 43 (GPCR43) on the intestinal epithelial cells (IECs) will reduce GVHD. 2. To analyze the molecular mechanisms for butyrate mediated resistance of intestinal epithelial cells (IECs) after allogeneic BMT. In this SA we will explore the hypothesis that the cell intrinsic oxidative metabolic state of IECs is critical for the butyrate mediated histone acetylation and epigenetic regulation of IECs resistance against damage after allogeneic. 3. To determine the impact of butyrate administration on GVL. In this SA we will test the hypothesis that administration of butyrate will mitigate inflammation and GVHD but retain sufficient GVL responses.
PROJECT 1 NARRATIVE Allogeneic hematopoietic stem cell transplantation is potentially a curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers. This project focuses on HDAC inhibition of GVHD.
| Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela et al. (2018) Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood Adv 2:1882-1888 |
| Ortiz-Velez, Laura; Ortiz-Villalobos, Javiera; Schulman, Abby et al. (2018) Genome alterations associated with improved transformation efficiency in Lactobacillus reuteri. Microb Cell Fact 17:138 |
| Ferrara, James L M; Chaudhry, Mohammed S (2018) GVHD: biology matters. Hematology Am Soc Hematol Educ Program 2018:221-227 |
| Major-Monfried, Hannah; Renteria, Anne S; Pawarode, Attaphol et al. (2018) MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood 131:2846-2855 |
| Naymagon, Steven; Naymagon, Leonard; Wong, Serre-Yu et al. (2017) Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol 14:711-726 |
| Hartwell, Matthew J; Özbek, Umut; Holler, Ernst et al. (2017) An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight 2:e89798 |
| Stickel, N; Hanke, K; Marschner, D et al. (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732-2741 |
| Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451 |
| Miller, Holly K; Braun, Thomas M; Stillwell, Terri et al. (2017) Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:522-528 |
| Holtan, Shernan G; Khera, Nandita; Levine, John E et al. (2016) Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors. Blood 128:2350-2358 |
Showing the most recent 10 out of 231 publications
