REG3α as a biomarker and therapeutic target for GVHD
Graft-versus-host-disease (GVHD) is a life-threatening complication of allogeneic BM transplantation that affects skin, liver, and the gastrointestinal (GI) tract. GI involvement is associated with the most severe form of disease and outcomes for these patients are poor. Treatments for GVHD are limited; therefore, a better understanding of markers of GI involvement have potential to improve treatment. In this episode, James Ferrara and colleagues identify the Paneth cell protein regenerating islet-derived 3α (REG3α) as a biomarker that is upregulated in sera of patients with GI GVHD. Moreover, using murine models, the authors determined that REG3α, which has well-known antimicrobial function, promotes intestinal stem cell survival; thereby, protecting the intestinal barrier. Together, these results indicate that strategies to increase REG3α should be explored for limiting GI GVHD.
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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 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 absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ 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 REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ 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.
Authors
Dongchang Zhao, Yeung-Hyen Kim, Seihwan Jeong, Joel K. Greenson, Mohammed S. Chaudhry, Matthias Hoepting, Erik R. Anderson, Marcel R.M. van den Brink, Jonathan U. Peled, Antonio L.C. Gomes, Ann E. Slingerland, Michael J. Donovan, Andrew C. Harris, John E. Levine, Umut Ozbek, Lora V. Hooper, Thaddeus S. Stappenbeck, Aaron Ver Heul, Ta-Chiang Liu, Pavan Reddy, James L.M. Ferrara
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)