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

Survival signal REG3α 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 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 2

Time course of REG3γ and IL-22 expression during GVHD.

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Time course of REG3γ and IL-22 expression during GVHD. (A–C) B6D2F1 mice...
(A–C) B6D2F1 mice underwent BMT from syngeneic B6D2F1 donors (no GVHD, white circles) or allogeneic B6 donors (GVHD, black or blue circles), and samples were analyzed on days +3, +7, and +14 after BMT (n = 5 for each group on each day). (A) Serial REG3γ levels in the serum as measured by ELISA. (B) Serial average Paneth cell numbers per HPF in ileal tissue. (C) Serial Reg3g and IL-22 mRNA expression in the ileum was measured by qPCR. (D–G) B6D2F1 mice underwent BMT, without irradiation conditioning, from syngeneic B6D2F1 donors (no GVHD, white triangles) or allogeneic B6 donors (GVHD, black triangles). (D–F) Serial body weight measurement (D), clinical GVHD score (E), and survival (F) of mice after BMT. (G) Serial Reg3g mRNA expression in the ileum on days +3, +7, and +14 after BMT (n = 6 for each group on each day). *P < 0.05, **P < 0.01, unpaired 2-tailed t test (A–E and G); **P < 0.01, log-rank test (F). (H–K) Following irradiation, B6 mice received 5.0 × 106 BM cells plus 0 × 106 to 5.0 × 106 T cells, as indicated, from C3H.SW donors. Samples were analyzed on day +7 after BMT (n = 4 for each group). (H) Body weight measurement. (I) Clinical GVHD score. (J) Serum REG3γ levels. (K) Reg3g mRNA expression in the ileum. *P < 0.05, **P < 0.01, 1-way ANOVA. Data are expressed as mean ± SEM.