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Survival signal REG3? prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

ABSTRACT: Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3? (REG3?) is a biomarker specific for GI GVHD. REG3? serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3? (the mouse homolog of human REG3?), and the absence of REG3? in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3? production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g-/- mice. In vitro, addition of REG3? reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3?/? to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.

SUBMITTER: Zhao D

PROVIDER: S-EPMC6205404 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

Zhao Dongchang D Kim Yeung-Hyen YH Jeong Seihwan S Greenson Joel K JK Chaudhry Mohammed S MS Hoepting Matthias M Anderson Erik R ER van den Brink Marcel Rm MR Peled Jonathan U JU Gomes Antonio Lc AL Slingerland Ann E AE Donovan Michael J MJ Harris Andrew C AC Levine John E JE Ozbek Umut U Hooper Lora V LV Stappenbeck Thaddeus S TS Ver Heul Aaron A Liu Ta-Chiang TC Reddy Pavan P Ferrara James Lm JL

The Journal of clinical investigation 20180924 11

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the abse ...[more]

PMID: 30106382

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Project description:Upper gastrointestinal acute graft-versus-host disease is reported in approximately 30% of hematopoietic stem cell transplant recipients developing acute graft-versus-host disease. Currently classified as Grade II in consensus criteria, upper gastrointestinal acute graft-versus-host disease is often treated with systemic immunosuppression. We reviewed the Center for International Blood and Marrow Transplant Research database to assess the prognostic implications of upper gastrointestinal acute graft-versus-host disease in isolation or with other acute graft-versus-host disease manifestations. 8567 adult recipients of myeloablative allogeneic hematopoietic stem cell transplant receiving T-cell replete grafts for acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome between 2000 and 2012 were analyzed. 51% of transplants were from unrelated donors. Reported upper gastrointestinal acute graft-versus-host disease incidence was 12.1%; 2.7% of recipients had isolated upper gastrointestinal acute graft-versus-host disease, of whom 95% received systemic steroids. Patients with isolated upper gastrointestinal involvement had similar survival, disease-free survival, transplant-related mortality, and relapse as patients with Grades 0, I, or II acute graft-versus-host disease. Unrelated donor recipients with isolated upper gastrointestinal acute graft-versus-host disease had less subsequent chronic graft-versus-host disease than those with Grades I or II disease (P=0.016 and P=0.0004, respectively). Upper gastrointestinal involvement added no significant prognostic information when present in addition to other manifestations of Grades I or II acute graft-versus-host disease. If upper gastrointestinal symptoms were reclassified as Grade 0 or I, 425 of 2083 patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation.

Dataset Information

Survival signal REG3? prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

Publications

Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease.

Similar Datasets

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