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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:ObjectiveTo determine the safety and efficacy of vedolizumab for the prophylaxis and treatment of gastrointestinal involvement of acute graft-versus-host disease (GVHD) (GI-aGVHD).MethodsLiterature search within PubMed, EMBASE, Web of Science, and Cochrane Library for observational studies and clinical trials that evaluated the effect of vedolizumab on GI-aGVHD was done through 17 May 2022. A bivariate and random-effect meta-analysis derived the pooled observational percentages and pooled risk ratios (RRs) from baseline of primary endpoints including overall response, complete response, mortality, and adverse events.ResultsThere was a total of 122 participants in eight eligible studies, including one study on the prophylactic use of vedolizumab and seven studies on vedolizumab for the treatment of GI-aGVHD. Of seven studies that reported details on baseline grades of GI-aGVHD, a total of 47 patients (47.95%) were of stage 4, 31 patients (31.63%) were of stage 3, 10 patients (10.2%) were of stage 2, and 10 patients (10.2%) were of stage 1. The use of vedolizumab for the treatment of GI-aGVHD yielded a significantly improved objective response rate (ORR) at 14 days (pooled ORR = 60.53%, pooled RR = 14.14, 95% CI: 2.95-67.71), 28 days (pooled ORR = 50%, RR = 7.36, 95% CI = 2.14-25.37), and 12 months (pooled ORR = 76.92%, RR = 13.66, 95% CI = 3.5-53.35) from baseline. Likewise, the use of vedolizumab was followed by a significantly improved complete response (CR) at 12 months (pooled CR = 27.27%, RR = 5.50, 95% CI = 1.01-29.95), yet the CR at 14 days and 28 days did not reach statistical significance. Fifty-seven out of 87 (pooled overall survival, OS = 34.5%) and 46 out of 65 (pooled OS = 29.2%) patients expired at 6 and 12 months after the use of vedolizumab, respectively. Prophylactic use of vedolizumab was not associated with any specific type of reported adverse events, while patients with GI-aGVHD on vedolizumab presented with significantly increased risks of adverse events including infections (RR = 7.55) and impaired metabolism or nutritional complications (RR = 9.00). All analyses were of a low heterogeneity (all I-squares = 0%).ConclusionVedolizumab was safe and effective for the prophylaxis and management of early grade GI-aGVHD. More clinical evidence is warranted to validate these findings.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345584, identifier CRD42022345584.

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.

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