5th Annual BMRP Investigator Meeting - Abstract

Insights into the Function of the NOD2 Gene in Intestinal Innate Immunity from Studies of Human Small Bowel Transplantation

Thomas Fishbein, Gennadiy Novitskiy, Denver Lough and Michael Zasloff^a

Transplant Institute, Department of Surgery, Georgetown University School of Medicine (Washington, D.C., U.S.A.)

Intestinal transplantation is a life-saving therapy.  Small intestinal graft rejection, which resembles Crohn’s disease (CD) clinically and pathologically, remains an unpredictable complication. Three polymorphisms in the NOD2 gene product - a microbial sensor- have been shown to increase the risk of CD.  We addressed the impact of CD-associated polymorphisms on the outcome of intestinal transplants.  Surprisingly, of 34 consecutive transplant recipients, 12 (39%) possessed NOD2 polymorphisms, a frequency similar that observed in CD, while only 3 of 37 (12%) donors had comparable mutations.  Transplant recipients were individuals who previously required extensive surgical resection of the small intestine, generally for disorders such as malrotation, intestinal atresia, or dysmotility; donors were individuals who sustained deadly trauma.  The severity of rejection, graft loss, infections, and death were significantly higher in recipients with CD-associated polymorphisms compared to recipients with wild type NOD2 loci.  Allografts placed into recipients with NOD2 mutant loci exhibited depressed mRNA levels of several intestinal epithelial antimicrobial peptides previously shown to be depressed in CD.  Our study suggests that CD-associated polymorphisms in the NOD2 gene in an intestinal allograft recipient represent a risk factor for severe rejection, graft loss, infections and death following intestinal transplantation.  Hematopoietic cells expressing NOD2 might play a role in maintaining the health of the innate immune defenses of the gut epithelium.  We will discuss evidence that NOD2 expressing dendritic cells or macrophages might communicate with the intestinal stem cell to dynamically modulate the cellular characteristics of the gut epithelium.

^aPrincipal Investigator