A systematic search was conducted in Medline and Embase databases using [“small bowel”, “ intestine”, “transplantation”, “organ transplants”, “allograft injury”, “chronic rejection”, “long term survival”] as search terms, identifying 514 abstracts. Based on the current understanding of CR, the following inclusion criteria were adopted by two independent reviewers: (i) CR supported by histological examination and (ii) clinical features of CR such as weight loss, diarrhea, motility dysfunction.

Results:

64 articles met the inclusion criteria. The majority of studies (48) were performed in rats, followed by dogs (11), pigs (3) and mice (2). Orthotopic intestinal transplantation was most frequent (52 studies), heterotopic transplantation was performed in 13 studies and 5 studies included the liver in the allograft. Historically, most rat models used the high responder combination BN to Lewis, but recently a low-responder combination model (Fischer F344 to Lewis) with initial Tacrolimus immunosuppression was described. Gold standard to assess CR was histology with vasculopathy and parenchymal fibrosis as pathognomonic features. Recently, analysis of inflammatory cell populations or cytokines by flow cytometry and qPCR in addition to functional parameters such as graft contractility or intracellular electrical activity were also employed. Episodes of severe acute rejection or infection seemed to accelerate CR. Attempts to induce donor specific tolerance by bone marrow chimerism or liver-including grafts showed mixed results and immunosuppressive therapy ameliorated CR in the experimental setting with varying efficacy.

 

Conclusions: The differences in the employed models (e.g. species, strain combination, transplant method, graft preservation, evaluation, immunosuppression) highlight different aspects of CR in intestinal allografts. The orthotopic rat model is a practical tool to evaluate the current hot topics in CR research, for example the role of innate immunity and pathogenetic significance of donor specific antibodies for chronic graft dysfunction.