6th Annual BMRP Investigator Meeting - Abstract

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.)

 

In a previous report we described an aggressive form of small intestinal allograft rejection observed in recipients who have Crohn’s disease associated mutations in their NOD2 alleles. Rejection responds to augmented immunosuppression unpredictably, and the likelihood of graft loss and death is many-fold higher than observed in recipients with a NOD2 wild type genotype. We have reported that within several weeks of transplantation, prior to any visible pathological change in the mucosa of the donor bowel, several antimicrobial peptides expressed by the Paneth cells of the donor bowel, such as HD5, decrease in abundance. Failure to sustain the normal level of epithelial antimicrobial peptides was observed only in the recipients with NOD2 mutations associated with Crohn’s disease. We speculated that in this recipient population, NOD2 expressing cells of the recipient, such as the dendritic cell, normally designed to sense microbes in the lumen and transduce the information through cytokine expression, fail to fulfill this function. One consequence is the inadequate production of certain AMPs required to prevent microbial access to the epithelium and perhaps to influence the species diversity of the luminal bacteria. A secondary inflammatory response is mounted leading to progressive destruction of mucosa. In this population of allograft recipient, the pathophysiology of rejection resembles the mechanisms proposed to explain the ileal form of Crohn’s disease.

 

In this presentation we describe a second distinguishable rejection process that appears to unfold in recipients with a wild type NOD2 genotype. The earliest phase of rejection is characterized by a secretory diarrhea. Mature enteroendocrine cells are significantly depleted, while goblet and Paneth cells are present in pre-rejection densities.  Progenitors of the enteroendocrine cell (EEC) expressing neurogenin-3 (NEUROG3) were found to be disproportionately reduced in numbers, along with their more mature EEC derivatives expressing neuro D; cells expressing the enteric hormones PYY and GLP-1 were profoundly depleted. The affected EEC lineage was not lost to apoptosis, the hallmark of rejection. Steroid treatment resulted in resolution of clinical symptoms, restoration of normal patterns of EEC differentiation, and recovery of normal levels of enteric hormones.

 

Our study supports a picture of the human intestinal epithelium as a “dynamic” cellular layer, capable of changing its cellular composition during postnatal life. The extent to which normal patterns of epithelial renewal are disturbed in IBD, as observed in intestinal allograft rejection, remains to be explored.

^aPrincipal Investigator