title: 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.
  
  
  CONCLUSIONS
  Crohn's disease-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunological risk factor for intestinal allograft rejection. Compromised epithelial defences precede visible epithelial injury and inflammatory infiltration. The association of impaired epithelial immunity with the recipient's genotype suggests that certain NOD2-expressing cells of haematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial AMPs within the allograft.
authors.affiliation: Transplant Institute, Georgetown University Hospital, Washington, DC, USA.
authors.forename: T
authors.initials: T
authors.lastname: Fishbein
authors.forename: G
authors.initials: G
authors.lastname: Novitskiy
authors.forename: L
authors.initials: L
authors.lastname: Mishra
authors.forename: C
authors.initials: C
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Kaufman
authors.forename: S
authors.initials: S
authors.lastname: Goyal
authors.forename: K
authors.initials: K
authors.lastname: Shetty
authors.forename: L
authors.initials: L
authors.lastname: Johnson
authors.forename: A
authors.initials: A
authors.lastname: Lu
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.forename: B
authors.initials: B
authors.lastname: Kallakury
authors.forename: D
authors.initials: D
authors.lastname: Lough
authors.forename: M
authors.initials: M
authors.lastname: Zasloff
mesh_terms: D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007421:Intestine, Small / Q000276:immunology* / Q000637:transplantation*; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016896:Treatment Outcome; D023083:beta-Defensins / Q000378:metabolism
chemical_list: D053473:Nod2 Signaling Adaptor Protein; D023083:beta-Defensins