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Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease
Dongchang Zhao, … , Pavan Reddy, James L.M. Ferrara
Dongchang Zhao, … , Pavan Reddy, James L.M. Ferrara
Published August 14, 2018
Citation Information: J Clin Invest. 2018;128(11):4970-4979. https://doi.org/10.1172/JCI99261.
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Concise Communication Immunology

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

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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

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Figure 1

REG3α/γ levels in the plasma/serum and intestinal mucosa during GVHD.

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REG3α/γ levels in the plasma/serum and intestinal mucosa during GVHD.
(A...
(A–C) Samples were collected from 28 allogeneic BMT patients without GVHD (white circles, n = 13) and with GVHD (black circles, n = 15). (A) Plasma concentrations of REG3α measured by ELISA. (B) Average Paneth cell numbers per high-power field (HPF) in the same biopsies. (C) Semiquantitative REG3α expression in the duodenum. (D–F) B6 mice underwent BMT from syngeneic B6-Ly5.1 donors (GVHD –, white circles, n = 7) or allogeneic C3H.SW donors (GVHD +, black circles, n = 7), and samples were analyzed on day +7 after BMT. (D) Serum REG3γ levels measured by ELISA. (E) Average Paneth cell numbers per HPF in ileal tissue from the same mice. (F) Ileal tissue Reg3g mRNA expression measured by quantitative PCR (qPCR). (G–I) B6D2F1 mice underwent BMT from syngeneic B6D2F1 donors (GVHD –, white circles, n = 6) or allogeneic B6 donors (GVHD +, black circles, n = 6), and samples were analyzed as before on day +7 after BMT. (G) Serum REG3γ levels. (H) Average Paneth cell numbers per HPF in ileal tissue. (I) Ileal tissue Reg3g mRNA expression. **P < 0.01, unpaired 2-tailed t test. Data are expressed as mean ± SEM.

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