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Presenter: Thomas M., Fishbein, washington, United States
Authors: Thomas Fishbein1, Denver Lough1, Juan Francisco Guerra1, Cal Matsumoto1, Kirty Shetty1, Stuart Kaufman1, Cheryl Little1, Michael Zasloff1
Thomas Fishbein, Denver Lough, Juan Francisco Guerra, Cal Matsumoto, Kirty Shetty, Stuart Kaufman, Cheryl Little, Michael Zasloff
Georgetown Transplant Institute, Washington, DC, United States
We have reported recently that the risk of immunological rejection is almost 100-fold greater in recipients who carry any of the prevalent NOD2 polymorphisms associated with Crohn’s disease, and have shown that the normal levels of a key antimicrobial peptide produced by the Paneth cells of the allograft, fall as the graft becomes repopulated by hematopoetic cells of the NOD2 mutant recipient. These studies are extended in this report. We show that within several months following engraftment into a NOD2 mutant recipient the allograft loses its capacity to prevent adherence of lumenal microbes. Despite the marked increase in expression of CX3CL1, a stress protein produced by the injured enterocyte, NOD2 mutant CX3CR1+ dendritic cells within the submucosa fail to exhibit their characteristic morphological phenotype. In addition, the mRNA and protein expression profiles of these LPDCs are also significantly distorted, including under-expression of genes within the TLR, ICAM and MIF families and over expression some inflammatory cytokines, such as IFN-γ and TNF-α. Finally, the NOD2 mutation within the CX3CR1+ LPDC appears to depress Wnt 5a expression both in vivo and in response to ex vivo MDP stimulation. We propose that the CX3CR1+ LPDC normally helps support normal Paneth cell function through expression of Wnt 5a, and that this function is impaired in the setting of intestinal transplantation into a NOD2 mutant recipient. The therapeutic value of Wnt 5a administration in this setting is proposed.
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