Permeability Changes in Small Bowel Allograft Rejection

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DESCRIPTION (provided by applicant): SB transplantation is a potential solution for patients with intestinal failure who otherwise will need lifelong parenteral nutrition. However allograft rejection and excessive infectious complications continue to limit its wider application. SB allograft rejection is associated with an increased epithelial permeability that facilitates translocation of bacterial products, that augment rejection and ultimately contribute to systemic sepsis, multiorgan failure and death. The molecular basis for this rejection mediated mucosal barrier defect is not known. We have established a mouse model of SB transplantation to evaluate SB allograft rejection and its consequences. Using this model we have demonstrated that increased permeability occurs early in early SB allograft rejection and is associated with changes in epithelial tight junction associated proteins. Since crypt cells are associated with weaker tight junctions, concurrent decreases in the villus to crypt ratio may also contribute to rejection mediated permeability. We have therefore proposed experiments that will better define the relationship between changes in epithelial tight junction barrier function and epithelial differentiation in early SB allograft rejection. Furthermore, early rejection is associated with the induction of TH1 cytokines and chemokines that perpetuate rejection by inducing an inflammatory response in intestinal epithelial cells. NF-KB mediates inflammatory changes in many cell types, including epithelial cells. In mouse SB allografts, we have demonstrated that epithelial NF-KB activation correlates with rejection mediated permeability changes. To further study the role of NF-KB in rejection mediated permeability changes we have developed a double transgenic mutant mouse with an enterocyte-specific IkB mutation (mIKBalpha) that acts as an NF-KB superrepressor. SB transplants performed using this mouse as a donor are associated with significant downregulation of NF-KB dependent, enterocyte specific proteins and delayed allograft rejection. We propose to exploit the mIKBalpha double transgenic mouse in a mouse SB transplant model to determine if graft enterocyte specific NF-KB signaling plays a role in rejection mediated changes in epithelial permeability and tight junction associated proteins in early SB allograft rejection.