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

J Clin Invest. 2018 Nov 1;128(11):4970-4979. doi: 10.1172/JCI99261. Epub 2018 Sep 24.


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.

Keywords: Adaptive immunity; Bone marrow transplantation; Immunology; Innate immunity; Transplantation.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Bone Marrow Transplantation*
  • Cell Survival / genetics
  • Colon / metabolism*
  • Colon / pathology
  • Female
  • Graft vs Host Disease / metabolism*
  • Graft vs Host Disease / pathology
  • Humans
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pancreatitis-Associated Proteins / genetics
  • Pancreatitis-Associated Proteins / metabolism*
  • Paneth Cells / metabolism*
  • Paneth Cells / pathology
  • Prospective Studies
  • Signal Transduction*
  • Transplantation, Homologous


  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Reg3g protein, mouse