Overview of Acute Small Bowel Allograft Rejection

Small bowel transplantation has being increasingly performed to treat patients with irreversible intestinal failure. However, the longtern outcome is still unsatisfactory compared with transplantation of other solid organs. This is largely because of the inability to completely control rejection, which often results in graft loss due to severe acute rejection as well as subsequent lethal infections secondary to heavy immunosuppression. Therefore, accurate diagnosis and treatment of acute rejection is critical in the management of patients receiving small intestine transplantation.

The recognition and diagnosis of acute intestinal rejection depends upon clinical observation, endoscopic examination, and the analysis of endoscopically-guided mucosal biopsy specimens. Because intestinal rejection, if not treated promptly, can rapidly increase in severity and result in graft loss or mortality, early detection and treatment is essential. Several biochemical and functional markers of rejection have been proposed in experimental animal models, but they are not generally practical in the clinical setting.

Overall, most patients experience one or more episodes of acute rejection. The onset is typically between post-transplant day 5 and 60, but late rejection is not uncommon, particularly if the immunosuppression has been decreased for some reason. The clinical features include fever, nausea and vomiting, diarrhea, abdominal pain and distension. The volume of stomal effluent increases and becomes watery. In some cases the presentation can entail septic shock with metabolic acidosis, hypotesion, and adult respiratory distress syndrome; this likely results from loss of mucosal integrity and bacterial translocation across the intestinal wall. Endoscopic appearances range from edema and hyperemia in mild instances to granularity, loss of the fine mucosal vascular pattern and diminished peristalsis to mucosal ulceration in more severe cases. Often the changes are patchy, and thus multiple biopsy samples are required.

Intestinal transplantation is unique because of the complex immunologic events which follow transplantation of a lymphoid organ. For the graft to function successfully, the donor mucosal immune system must be replaced by the host and a chimeric state is essential for the allograft to continue to function. The early processes of immunologic reactions after transplantation include the infiltration of the graft by recipient lymphocytes and the subsequent repopulation of the graft's donor gut-associated lymphoid tissue (GALT) by recipient cells. This process occurs over weeks to months after transplantation. Unless alloreactivity is controlled by adequate immunosuppression, the infiltrated GALT areas become sites of intense immune stimulation and the inflammatory infiltrate begins to extend into the lamina propria and results in epithelial damage and crypt cell apoptosis. As a result of this process, tissue damage -- referred to as acute rejection -- develops. The normal distribution of GALT likely explains why acute rejection is distributed in a patchy fashion and most commonly involves the ileum. The complex immunologic events following transplantation of the lymphoid tissue-rich small intestine also explains why heavy immunosuppression is required for patients receiving the small bowel allografts.

The histologic diagnosis of acute intestinal rejection is based on a varying combination of three main features, each of which is illustrated in the accompanying figures: (1)infiltration by a mixed but primarily mononuclear inflammatory population including blastic or activated lymphocytes; (2)crypt injury (characterized by cytoplasmic basophilia, nuclear enlargement and hyperchromasia, decreased cell height and mucin depletion) and inflammation; and (3)increase in crypt apoptotic bodies. As a general rule, early acute rejection episodes (usually within the first 100 days after transplantation) tend to be associated with a greater degree of inflammatory infiltration and less conspicuous apoptosis, while in later rejection episodes, the converse is often seen. The following mechanisms explain the morphological difference between the early and later rejection: in early acute rejection the infiltration of donor GALT by recipient's lymphocytes with intense inflammatory reaction is the predominate process; in later rejection episodes the allograft GALT has already been replaced by recipient lymphoid cells and the immune reactivity is directed primarily at the epithelial and stromal cells.

Crypt cell apoptosis is a process important for the physiologic regulation of the intestinal epithelium which is far more extensive in rejection Apoptotic bodies are characterized by fragmented nuclear debris and cytoplasm contained within a rounded vacuole. The apoptotic bodies should be distinguished from small isolated fragments of nuclear chromatin and intraepithelial neutrophils and eosinophils. We count the apoptotic bodies by scanning the specimen at medium power to identify areas of the greatest concentration and then tallying the total number in 10 consecutive crypts. Although a common feature of rejection, the apoptotic bodies are not specific: Rare apoptotic bodies can be identified in normal mucosa and their number is increased in many inflammatory and immunologic processes including graft-versus-host disease. Nonetheless, normal mucosa generally demonstrates 2 or fewer apoptotic bodies per 10 crypts, whereas counts of more than 5 per 10 crypts are seldom seen except in allograft rejection. It should be remembered, however, acute rejection is associated with a wide range of apoptotic bodies counts, and therefore the overall findings and context needs to be taken into account. It is likely that several mechanisms are responsible for crypt cell apoptosis and the molecules important in this process may include IL-1, TNF-a, Fas, CD40, and cytotoxic T cells. An alternative mechanism is that apoptosis may represent merely a nonimmunologic homeostatic process, occurring as a response to increased crypt cell proliferation after epithelial injury.

Once a diagnosis of acute rejection has been secured, its severity can be graded as indeterminate, mild, moderate and severe based on the extent of mucosal injury, the degree of inflammatory infiltration and cyrpt apoptosis, as detailed in the figures. Indeterminate for acute rejection is used when the biopsy shows the three main features of acute rejection, but the changes do not meet the criteria for mild acute rejection. It should not be used when one is uncertain whether a biopsy represents non-specific inflammation, infection or other non-rejection etiologies. In addition to this histologic assessment, attention should be paid to the endoscopic findings, since this provides an overall estimation of distribution and magnitude of graft injury. For example, a solitary ulcer near the ileostomy stoma for duration of several weeks with no clinical symptoms is unlikely to represent a moderate or severe acute rejection.

Most centers routinely perform surveillance endoscopies through ileostomies with additional procedures when clinically indicated. Since biopsies obtained close to the ileostomy stoma often have non-specific inflammatory or regenerative changes, endoscopists should be encouraged to obtain biopsies away from the stoma. As already mentioned above, because intestinal allograft rejection is often patchy, biopsies from different regions including visually involved and noninvolved areas should be performed to ensure specimen adequacy. In addition, as acute cellular rejection often involves crypts and the graft's donor gut-associated lymphoid tissue, the endoscopic biopsies should be deep enough to include sufficient crypts for evaluation and ideally also include muscularis mucosae and the upper portion of submucosa.

The treatment options for histologically diagnosed acute rejection require close clinicopathologic correlation. Acute rejection of the small bowel allograft, if not treated early, can rapidly increase in severity. In fact, despite aggressive immunosuppressive therapy, most of the patients with histologically diagnosed severe acute rejection will continue to progress to graft loss or mortality. Therefore, it is extremely important to diagnose acute rejection early and treat it effectively. While mild acute rejection usually requires an increase in immunosuppressive drugs with close clinical observation, a more aggressive immunosuppressive therapy should be initiated for moderate or severe episodes of acute rejection. It is a clinical decision whether to treat indeterminate for acute rejection. While the latter situation may or may not require increased immunosuppressive therapy depending on clinical situations as well as the experience in individual institutions, it mandates careful clinical observation and close endoscopic follow-up.

REFERENCES

Wu, T., Abu-Elmagd, K., Bond, G., Nalesnik, M. A., Randhawa, P., and Demetris, A. J. A schema for histologic grading of small intestine allograft acute rejection. Transplantation, 75: 1241-1248, 2003.

Wu, T., Bond, G., Dolly, M., Nalesnik, M. A., Demetris, A. J., and Abu-Elmagd, K. Histopathologic characteristics of human intestine allograft acute rejection in patients pretreated with thymoglobulin or alemtuzumab. Am J Gastroenterol, 101: 1617-1624, 2006.

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Lee RG, Nakamura K, Tsamandas AC, Abu-Elmagd K, Furukawa H, Hutson WR, Reyes J, Tabasco-Minguillan JS, Todo S, Demetris AJ. Pathology of human intestinal transplantation. Gastroenterology 1996;110:1820-1834.

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