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Intestinal transplantation (ITx) remains a lifesaving option for patients suffering from irreversible intestinal failure and complications from total parenteral nutrition. Since its inception, it became obvious that intestinal grafts are highly immunogenic, due to their high lymphoid load, the abundance in epithelial cells and constant exposure to external antigens and microbiota. This combination of factors and several redundant effector pathways makes ITx immunobiology unique. To this complex immunologic situation, which leads to the highest rate of rejection among solid organs (>40%), there is added the lack of reliable non-invasive biomarkers, which would allow for frequent, convenient and reliable rejection surveillance. Numerous assays, of which several were previously used in inflammatory bowel disease, have been tested after ITx, but none have shown sufficient sensibility and/or specificity to be used alone for diagnosing acute rejection. Herein, we review and integrate the mechanistic aspects of graft rejection with the current knowledge of ITx immunobiology and summarize the quest for a noninvasive biomarker of rejection. [ABSTRACT FROM AUTHOR]

Chronic rejection affects the long-term survival of all solid organ transplants and, among intestinal allografts, occurs in up to 10% of the recipients. The insidious clinical evolution of the chronic allograft enteropathy, the absence of noninvasive biomarkers, and the late endoscopic findings delay its diagnosis. No pharmacological approach has been proven effective, and allograft removal nowadays still represents the only available therapy. The inclusion of the liver in the visceral allograft appears to be the only intervention affecting the development of chronic rejection, as revealed by large-center studies and registry reports. A significant body of evidence emerged from the experimental setting and provided essential knowledge on the complex mechanisms behind the development of chronic allograft enteropathy. More recently, donor-specific antibodies have been suggested as an early, key element in the natural history of chronic allograft enteropathy and several novel approaches, tackling the antibody-mediated graft injury, have gained acceptance in clinical settings and are believed to impact on chronic rejection. The inclusion of a liver allograft is advocated when re-transplanting a sensitized recipient, due to its protective effect against humoral immunity. Multicenter trials are required to understand and tackle chronic rejection, and find the therapeutic answer to this clinical dilemma. [ABSTRACT FROM AUTHOR]

Background Mucosal barrier injury during intestinal preservation (IP) and transplantation favors life-threatening infections. Luminal delivery of solutions containing amino acids or polyethylene glycols (PEGs) may improve preservation results and reduce this injury. We tested if solutions containing glutamine and PEG influence the mucosal injury. Materials and methods Rat intestines were perfused and stored in Viaspan-University of Wisconsin solution. Before IP, a PEG 3350 solution was introduced intraluminally alone (group 1) or supplemented with 40 mmol/L L-glutamine (group 2). Controls underwent vascular flush alone (group 3). Preservation injury was evaluated after 8, 14, and 24 h by histology and goblet cell count. Tight-junction proteins zonula occludens-1, claudin-3, claudin-4, and caveolin-1 were studied by immunofluorescence. Maltase and caspase-3 activity were also analyzed. Results Group 1 showed mild edema at 8 h and mucosal disruption by 24 h; these features were greatly improved in group 2 where continuous mucosa was found after 24 h of IP. Intestines in group 3 did worse at all time points with subepithelial edema (Park/Chiu grade 3) and marked goblet cell depletion; caspase-3 activity was lowest in group 2. Tight-junction proteins varied continuously during IP; zonula occludens-1 expression and colocalization with claudins decreased significantly in group 3 but not in other groups. Claudin-3 was distinctly localized in the membrane, but stained diffuse, cytoplasmic at later time-points. Claudin-4 changed to a cytoplasmic granular pattern. No caveolin-1 colocalization was observed. Conclusions Luminal PEG and glutamine delay epithelial breakdown and preserve several important mucosal features during extended IP. [ABSTRACT FROM AUTHOR]

Background: The postischemic intestine liberates pro-inflammatory mediators (cytokines, lipopolysaccharide [LPS], free radicals) proportional with the local injury that may trigger a systemic inflammatory response and multi-system organ failure. Previously, intestines from donors receiving Tacrolimus revealed improved morphology and abrogated nuclear factor kappa B (NF-κB) activation. Because of its pivotal role in inflammation, we investigated if NF-κB intragraft inhibition influences the posttransplant inflammatory response and remote organ injury. Materials and methods: Donor Sprague Dawley rats received tacrolimus (0.3 mg/kg) or saline i.v. 6 h before graft harvest. The intestines were preserved for 3 h and then transplanted heterotopically. Hepatic microcirculation was assessed at 20 min, 6 h, 12 h, or 24 h post-reperfusion (postR) using laser-Doppler flowmetry (n = 10/group). Blood pressure measurements and liver sampling were performed at 6, 12, or 24 h postR. Blood samples were obtained at 1, 3, 6, 12, and 24 h postR. Hepatic intercellular adhesion molecule 1 (ICAM-1) expression, caspase-3 and -9 activity, and circulating tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, and LPS were studied. Results: Pretreated graft (PG) recipients had superior cardiovascular parameters at 6 and 12 h postR, while liver perfusion was similar between groups at all time points. Recipients of PG had lower transaminase levels and ICAM-1 liver expression. Liver caspase 3 and 9 activity were similar at 6 and 12 h but increased at 24 h in both groups. At every time point, circulating tumor necrosis factor alph, IL-1β, and IL-6 were lower in animals receiving PG. LPS was found increased only at the last time point. Conclusions: Transplantation of tacrolimus-pretreated intestines triggered a milder inflammatory response and decreased liver injury early posttransplantation compared with untreated grafts. Cytokines, but not neutrophils, hypoperfusion, or LPS may underlie the dysfunction. [Copyright &y& Elsevier]

Introduction: Intestinal cold ischemia and subsequent reperfusion during transplantation result in various degrees of mucosal injury ranging from mild edema to extensive mucosal loss. Mucosal barrier impairment favors bacterial translocation and fluid loss and raises nutritional challenges. The injured intestine also releases proinflammatory mediators and upregulates various epitopes toward an inflammatory phenotype. We studied the process of mucosal injury and repair during the early period after intestinal transplantation from a histological and molecular standpoint. Materials and Methods: Adult Sprague-Dawley rats were used as donors and recipients. Donor intestines were perfused and stored in saline for 3 h, then transplanted heterotopically using microvascular anastomoses. Intestinal graft segments were obtained after 20 min, 6 h, 12 h, and 24 h after reperfusion. Histology studies (goblet cell count, morphometry), immunofluorescence, and western blot for several tight junction proteins, apoptosis, and inflammation-related proteins were performed. Results: Cold storage led to extensive epithelial detachment, whereas reperfusion resulted in extensive villus loss (about 60% of the initial length), and goblet cell numbers were drastically reduced. Over the first 24 h, gradual morphologic and molecular recovery was noted, although several molecular alterations persisted (increased apoptosis and inflammation, altered expression of several tight junctions). Conclusions: The current data suggest that a near-complete morphologic recovery from a moderate mucosal injury occurs within the first 24 h after intestinal transplantation. However, several molecular alterations persist and need to be considered when designing intestinal transplant experiments and choosing sampling and endpoints. [ABSTRACT FROM AUTHOR]

Objective. Intestinal and multivisceral transplantation have gained acceptance as treatment modalities for patients with: intestinal failure and life-threatening complications of parenteral nutrition (PN), rare cases of vascular abdominal catastrophes and selected cases of low-grade neoplastic tumors such as neuroendocrine pancreatic tumors and desmoids involving the mesenteric root. The aim was to describe the survival and nutritional outcome in the transplanted Nordic patients and the complications attributed to this procedure. Method. The authors included all Nordic patients transplanted between January 1998 and December 2013. Information on patients transplanted outside the Nordic region was collected through questionnaires. Results. A total of 34 patients received different types of intestinal allografts. Currently, there are two Nordic transplant centers ( n = 29) performing these procedures (Gothenburg, Sweden n = 24, Helsinki, Finland n = 5). The remaining five patients were transplanted in the USA ( n = 3) and the UK ( n = 2). Most patients were transplanted for life-threatening failure of PN (70%) caused primarily by intestinal motility diseases (59%). Allograft rejection was the most common complication and occurred in 79% of the patients followed by post-transplantation lymphoproliferative disorders (21%) and graft-versus-host disease (18%). The 1- and 5-year survival was 79% and 65% respectively for the whole cohort and nutritional autonomy was achieved in 73% of the adults and 57% of the children at 1 year after transplantation. Conclusion. This collective Nordic experience confirms that intestinal transplantation is a complex procedure with many complications, yet with the possibility to provide long-term survival in selected conditions previously considered untreatable. [ABSTRACT FROM AUTHOR]