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Guarding the gut against GVHD
The gastrointestinal tract is one of the major target organs of graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant. Goblet cells, mucus-secreting epithelial cells, are diminished in GVHD, but the pathophysiological implications were unknown. Ara et al. used mouse GVHD models to demonstrate that goblet cell loss disrupted the inner mucus layer of the colon and permitted bacterial translocation. GVHD was also exacerbated in mice lacking the antimicrobial Lypd8. Goblet cell preservation with IL-25 pretreatment maintained the gut barrier and blunted GVHD. In patient biopsies, goblet cell loss was associated with severe gastrointestinal GVHD and poor outcomes. Collectively, these results suggest that retaining goblet cells with IL-25 conditioning could prevent GVHD in the gut.
Abstract
Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.
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