Acute graft versus host disease (GVHD) is the major cause of non-relapse mortality (NRM) following allogeneic bone marrow transplantation (BMT). The GI tract is the GVHD target organ that is most difficult to treat. Studies from this P01 grant have identified and validated Regenerative 3 alpha (REG3?A) as a plasma biomarker specific for the GVHD of the GI tract. REG3?A (and its mouse homologue Reg3??) are antimicrobial peptides produced by intestinal epithelial cells that protect the barrier function and integrity of the intestinal mucosa. Our long term objective is to develop novel strategies to reduce the morbidity and mortality of GVHD. Our central hypothesis is that REG3?A functions as a master regulator of GI GVHD. We have formulated our hypothesis based on our own published data that show that the destruction of Paneth cells by GVHD correlates with NRM. Unpublished data show that GVHD suppresses production of Reg3?? in mice, and that mice deficient in Reg3?? suffer more severe GVHD than normal mice. Further preliminary data show that administration of IL-22 which induces Reg3??, restores endogenous Reg3?? and reduces GI GVHD. But in the absence of Reg3??, IL-22 loses its ability to protect mice from GVHD. Thus REG3?A/Reg3?? appears to be a master (negative) regulator of GVHD. Once the role of Reg3?? in the pathophysiology of GI GVHD is better understood, these mechanistic insights will lay the foundation for innovative approaches to prevent and treat GVHD through modulation of the epimmunome. We will test our central hypothesis and achieve the objective of this project by pursing the following two specific aims: 1. To define the mechanisms by which Reg3? reduces GVHD. We will examine effects of Reg3? on both intestinal epithelium and hematopoietic cells that drive T cell responses. In collaboration with Project 1 we will examine the role of butyrate in modulating Reg3? in its prevention of GVHD. We will also evaluate the effects of Reg3? on GVL effects. 2. To determine if Enterococcus drives GVHD. Using the gnotobiotic expertise in revised Core 2, have demonstrated that germ free (GF) mice do not develop severe GVHD after allogeneic BMT. Given the predominance of enterococcus in both severe GVHD in both humans and experimental models is both necessary and sufficient to cause GVHD using customized human microbial laboratories to customize GF mice. We will use advanced metagonomic sequencing techniques to correlate shifts in the microbiota with evolving GVHD status. 3. To determine the effects of the antibiotic treatment and therapeutic probiotics on GVHD severity. Early systemic antibiotic treatment is associated with more severe GVHD in humans and mice. Experiments in Core 2 have now shown that systemic antibiotics dramatically decrease Reg3? in mice. This SA we will test the hypothesis that the increased severity of GVHD after antibiotic treatment is mediated by a loss of Reg3?. The second subaim will test probiotics secreting IL-22 or REG3A to prevent GVHD. As shown in preliminary data of Core 2, prototypes of both probiotics are now in hand and ready for testing. We expect the studies proposed in this project to define the key functions of REG3A that regulate GI GVHD. This project possesses strong synergies with Project 1 in the evaluation of butyrate, which reduces apoptosis of GI epithelium and which induces antimicrobial peptides, for its ability to reduce GVHD. Further, synergies derive from the subaims evaluating pretreatment with systemic antibiotics and evaluation GVL effects, using the same tumors and antibiotics protocols, and experiments which will be closely coordinated between laboratories. This project also synergizes with Project 3 that will use biomarkers, including REG3A, to identify patients with high risk GI GVHD early in their disease course for novel therapeutic trials. The positive impact of this project will be to transform our understanding of GVHD and approach to this major complication of allogeneic BMT.
PROJECT 2 NARRATIVE Allogeneic hematopoietic stem cell transplantation is a potentially 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 a antimicrobial peptide, Regenerative 3 alpha, to modulate GVHD.
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|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|
|Renteria, Anne S; Levine, John E; Ferrara, James L M (2016) Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease. Expert Opin Orphan Drugs 4:469-484|
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