Organ-Specific Differences in Acute Rejection Intensity in a Multivisceral Transplant

Abstract

Multivisceral transplantation is a valuable treatment option for irreversible gastrointestinal disorders, although acute rejection remains a serious complication (1–4). We have previously reported on the pathology of small bowel (5) and stomach allograft (6) pathology but there is minimal information on synchronous rejection of all organs in a multivisceral transplant (2, 3). Herein we report the pathological findings of concurrent multiple allograft rejection in a multivisceral transplant. The patient was an 11-month-old female with history of short-gut syndrome due to necrotizing enterocolitis and liver failure due to total parenteral nutrition. She underwent multivisceral transplantation (stomach, pancreas, liver, duodenum, small intestine, and large intestine) in July 2005. Immunosuppression included tacrolimus and steroids. Moderate to severe acute rejection of the transplanted ileum was revealed 28 days posttransplant. The rejection was uncontrollable despite OKT 3 therapy. She underwent retransplantation 51 days posttransplant with replacement of all the previously transplanted organs. Grossly, the explanted allografts showed extensive adhesions and focal wall attenuation. The explanted liver and pancreas were macroscopically normal. Microscopic findings revealed (Fig. 1): liver, mild acute rejection (7); pancreas, minimal acute rejection (Grade II) (8); stomach, indeterminate for acute rejection (Grade IND); duodenum, moderate acute rejection (Grade 2) (6); proximal/distal small intestine, extensive loss of mucosa and crypts accompanied by marked congestion and mixed infiltrate consistent with severe exfoliative rejection (Grade 3) (3, 5); and large intestine, moderate acute rejection (Grade 2) (5). Immunofluorescence evaluation for immunoglobulins and complement (including C4d) revealed no evidence of a humoral component to the rejection. Early postoperative screening by endoscopic biopsy showed no allograft rejection after her second transplant. However, the patient died from severe respiratory distress 16 days after the second surgery.FIGURE 1.: Microscopic findings of the explanted allograft. (A) Liver: subendothelial lymphocytic infiltrate of the portal vein and lymphocytic cholangitis consistent with mild acute rejection. H&E, 200×. (B) Pancreas: minimal septal inflammatory infiltrates associated with endothelialitis consistent with minimal acute rejection. H&E, 200×. (C) Stomach: minimal increase in crypt apoptotic bodies consistent with indeterminate for acute rejection. H&E, 100×. (D) Duodenum: crypt epithelial cell apoptosis with confluent apoptosis, consistent with moderate acute rejection. H&E, 100×. (E and F) Proximal and distal small intestine: extensive loss of mucosa and crypts and replacement by granulation tissue consistent with severe “exfoliative” rejection. H&E, 100×. (G) Large intestine: crypt epithelial apoptosis with foci of “confluent apoptosis” with congestion and erythrocyte extravasation consistent with moderate acute rejection. H&E, 100×.Indirect evidence has implied that intestinal grafts are more susceptible to acute rejection as compared to other abdominal viscera (1, 2, 4). In our study, we have simultaneously compared multiple allograft organs and found differences in severity of acute rejection with small bowel being most severe. There are several potential mechanisms of how the inherent immunogenicity of an organ can differ. For example, the type of stimulatory molecules expressed (e.g., class II-MHC), the cellular composition (e.g., parenchymal vs. endothelial cells), the donor cell response to injury (e.g., cytokine release) can all contribute to the scope of available targets for immunological injury. Individual response to injury may make cells more susceptible to alloreactive T-cells (9). It is currently unclear which of these factors predispose small bowel to being more susceptible to rejection. Interestingly, retrospective studies have implied that there may be protective effects for the rejection of the small intestine allograft depending upon which other organs are transplanted (2, 4, 10–13), although the mechanism for this remains undetermined. In conclusion, our case illustrates contrasting susceptibility to acute rejection between abdominal allograft organs in multivisceral transplantation, the most predisposed being the small bowel. Further investigation is required to better understand the mechanism of this phenomenon. Hidenori Takahashi Gennaro Selvaggi Siego Nishida Debbie Weppler David Levi Tomoaki Kato Andreas Tzakis Department of Surgery University of Miami Miami, FL Phillip Ruiz Departments of Surgery and Pathology University of Miami Miami, FL