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Nod 2 expressing bone marrow derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine
  1. Thomas Fishbein (thomas.m.fishbein{at}medstar.net)
  1. Georgetown University School of Medicine, United States
    1. Gennadiy Novitskiy (gkn3{at}georgetown.edu)
    1. Georgetown University, United States
      1. Lopa Mishra (lm229{at}georgetown.edu)
      1. Georgetown University, United States
        1. Cal Matsumoto (cal.matsumoto{at}medstar.net)
        1. Georgetown University, United States
          1. Stuart Kaufman (stuart.f.kaufman{at}medstar.net)
          1. Georgetown University, United States
            1. Saurabh Goyal (s.goyal{at}yahoo.com)
            1. Georgetown University, United States
              1. Kirti Shetty (kirti.shetty{at}medstar.net)
              1. Georgetown University, United States
                1. Lynt Johnson (lynt.johnson{at}medstar.net)
                1. Georgetown University, United States
                  1. Amy Lu (amy.lu{at}medstar.net)
                  1. Georgetown University, United States
                    1. Antai Wang (aw94{at}georgetown.edu)
                    1. Georgetown University, United States
                      1. Fengming Hu (fh46{at}georgetown.edu)
                      1. Georgetown University, United States
                        1. Bhaskar Kallakury (kallakub{at}georgetown.edu)
                        1. Georgetown University, United States
                          1. Denver Lough (dml46{at}georgetown.edu)
                          1. Georgetown University, United States
                            1. Michael Zasloff (maz5{at}georgetown.edu)
                            1. Georgetown University, United States

                              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 our 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. We investigated whether epithelial immune function and graft survival were influenced by NOD2 mutations in our intestinal transplant population. Methods: We determined the NOD2 genotypes of 34 transplants performed consecutively at our center over the past 3 years. We related the NOD2 genotypes 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 to recipients with wild type NOD2 loci. Rejection in NOD2 mutant recipients was characterized by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation. Conclusions: CD-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunologic risk factor for intestinal allograft rejection. Compromised epithelial defenses 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 hematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial antimicrobial peptides within the allograft.

                              • Antimicrobial Peptides
                              • Intestinal Transplantation
                              • NOD2
                              • Paneth Cells
                              • innate immunity

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