NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine

Abstract

Background: Intestinal allograft rejection resembles Crohn's disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn's disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. Methods: The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. Results: An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation.

Human gut microbiome adopts an alternative state following small bowel transplantation

“…Although designation as a ''facultative'' or ''strict'' anaerobe cannot be assumed to apply to all members of a high-level bacterial taxon, these four particular bacterial orders are well characterized and are widely thought to fit these respiratory categorizations (19). Eight of the seventeen patients (1,2,3,5,8,11,13,16) (Fig. 1) have higher levels of strict anaerobes at very early time points; 75% of these (1,3,5,8,13,16) received a transplanted small bowel that had not been decontaminated and thus could have served as an inoculum.…”

“…The NOD2 protein plays a key role in intestinal immune health, specifically in the sensing of microbial products and the production of antimicrobial peptides by the Paneth cells of the intestine. The likelihood of allograft rejection and sepsis in SBT patients with mutant NOD2 genes is Ϸ100 times higher than in patients with the wild-type gene (3). Therefore, we undertook this study (1) to characterize the microbiota colonizing this severely traumatized small bowel and (2) to test for correlations between shifts in that microbiota and clinical factors such as NOD2 genotype.…”

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation

“…However, donor immune cells can indirectly lower the production of defensins 34 and also suffer from the 'loss of tolerance', so they could influence incidence and severity of aGVHD.…”

Current Immunosuppression in Abdominal Organ Transplantation

“…Mutations of NOD2 are highly correlated with Crohn's disease. We found that 35% of intestinal transplant recipients have NOD2 mutations associated with Crohn's disease and that the risk severe rejection and of graft failure were significantly greater in the NOD2 mutant recipients compared with the NOD2 wild-type recipients (Fishbein et al 2008). The presence of a NOD2 polymorphism in the recipient may influence the viability of the allograft by interrupting NOD2-dependent circuits required to maintain intestinal homeostasis with respect to commensal flora: a recipient lacking a functional intestinal microbial-sensing system may be more exposed to allograft damage secondary to rejection than a recipient with an intact system.…”