Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.
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PMID:The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. 2128 78

Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation. The gastrointestinal tract is a major target organ of GVHD, and disruption of the barrier function of the intestinal mucosa leads to an influx of danger signals derived from intestinal microbiota, which may further exaggerate GVHD. We have shown that the recombinant human R-spondin1 protects intestinal stem cells against GVHD, improves intestinal dysbiosis, and ameliorates GVHD. However, the endogenous R-spondin-producing cells in the small intestine remained to be studied in greater detail. This study clarified that R-spondin3 is the predominant R-spondin protein produced in the mouse small intestine. We also found that R-spondin3 is predominantly produced by lymphatic endothelial cells. Furthermore, we found that GVHD targets lymphatic endothelial cells in the small intestine, leading to decreased R-spondin3 production. GVHD-induced reduction of endogenous R-spondin3 could delay intestinal epithelial regeneration, possibly resulting in GVHD deterioration.
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PMID:[Graft-versus-host disease targets R-spondin3-producing lymphatic endothelial cells in the small intestine]. 3262 35