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

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 alpha (REG3 alpha) is a biomarker specific for GI GVHD. REG3 alpha serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3 gamma (the mouse homolog of human REG3 alpha), and the absence of REG3 gamma in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3 gamma 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 alpha reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3 alpha/gamma 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.