Intraluminal oxygen can keep small bowel mucosa intact in a segmental ischemia model.

Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel's appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation.

Luminal Preservation Protects the Small Intestine in a Brain-dead Rat Model.

Intestinal transplantation depends on donation after brain death (DBD). Luminal preservation (LP) has been beneficial against preservation injury in previous studies in animal models, but none include DBD. This study aims to investigate whether these benefits occur also with DBD. Methods: Wistar rats (male, N = 9) underwent brain death for 2 h. Thereafter, vascular perfusion was done with University of Wisconsin solution (UW). The small intestine was then explanted and randomized into 3 groups: control (empty segment), LP+PEG (with polyethylene glycol 3350 solution), or LP+UW (with UW), treated and tied shut. Ice-cold UW was used for cold storage. Samples were taken at procurement and after 4 (t = 4) and 8 h (t = 8) of preservation. Histopathological scorings were performed for intestinal preservation injury, subepithelial space, absence of epithelial lining, and hemeoxygenase-1 expression. Results: There was low-level mucosal injury (median intestinal preservation injury score 2) at procurement. At t = 4, bowels treated without LP had more damage than LP-treated samples (control score 4, LP+PEG 2 and LP+UW 2, P < 0.001 control versus LP+UW). At t = 8, no benefit of LP was observed (control 2, LP+PEG 3, LP+UW 2). Subepithelial space increased with time and the presence of LP; epithelial lining was better conserved in LP-treated samples. Hemeoxygenase-1 staining showed increased intensity with increased damage, irrespective of treatment. Conclusions: Luminal perfusion of the small intestine with UW or PEG protects the mucosa in brain-dead rats for up to 4 h. Fewer benefits of LP were found than previously described in non-DBD models. To mimic the clinical situation, DBD should be included in future animal studies on intestinal preservation.

Safe and Successful Treatment of Acute Cellular Rejection of an Intestine and Abdominal Wall Transplant With Vedolizumab.

Graft survival rates after intestinal transplantation (ITx) are still the lowest in comparison to other solid organ transplants. One of the main reasons is the frequent occurrence of acute cellular rejection (ACR). Vedolizumab is an antibody against α4ß7+ integrin involved in gut-homing of T cells which has been approved for inflammatory bowel diseases (IBD). We report its off-label use to treat ACR after ITx. METHODS: Following abdominal wall transplantation (AWTx) and ITx, clinical course was followed biochemically. Sequential small intestinal biopsies were taken preceding, during, and after ACR treatment with vedolizumab, following the standard therapy regime for IBD. Rejection was diagnosed histologically, and proinflammatory (α4ß7+, interleukin-17+) and regulatory (FoxP3+) T cells were analyzed by immunohistochemistry. RESULTS: ACR in both the ITx and AWTx resolved upon vedolizumab treatment, which was safe, evidenced by clearing an astrovirus and primary cytomegalovirus infection. Only a slight reduction of α4ß7+ cells in the mucosa was observed, and α4ß7+ and regulatory T cells could still move into the lamina propria upon infection. CONCLUSIONS: Vedolizumab is a safe treatment option for ACR after ITx but its mechanism is probably not only based on inhibition of gut-selective T-cell homing.

Current understanding of alloimmunity of the intestinal graft.

PURPOSE OF REVIEW: This review focuses on the known mechanisms of alloimmunity that occur after transplantation and what is being done in order to improve graft and patient survival, particularly in the long term. RECENT FINDINGS: The presence of mismatched antigens and epitopes might relate directly to the development of de-novo donor-specific antibodies (DSA), and thus, rejection. In an abdominal wall transplant, the skin graft could be the first to show signs of rejection. The epithelial or endothelial cells are the main targets in acute and chronic rejection, respectively. Possible therapeutical targets are gut homing T cells and cells of the innate immune system. Chimerism development might mostly occur in isolated lymph nodes, but also in the epithelium, particularly after transplantation of bone marrow mesenchymal stromal cells. SUMMARY: Ischemia-reperfusion, surgical injury, and bacterial translocation trigger the innate immune system, starting acute rejection. Interaction between donor and recipient immune cells generate injury and tolerance, which occur mostly in secondary lymphoid organs, lamina propria, and epithelium. Chronic rejection mostly affects the endothelial cells, generating graft dysfunction. DSA increase the risk of graft rejection both acutely and chronically, and the liver protects against their effects. Induction therapies deplete lymphocytes prior to implantation, and maintenance therapies inhibit T-cell expansion. Rejection rates are the lowest when depleting drugs and a combination of interleukin 2 receptor blockade, inhibition of T-cell expansion, and steroids are used as maintenance therapy. Chimerism and tolerogenic regiments that induce Tregs and prevent the development of DSA are important treatment goals for the future.