SIMULTANEOUS ISLET LIVER ALLOTRANSPLANTATION IN RATS

In a recent article, Wang et al. (1) report the results of a study in which they “examine the effect of liver transplantation on islet allografts in a rat model by comparing the survival times of islet allografts with or without liver allografting” using a strain combination in which liver allografts are spontaneously accepted across a full MHC barrier. This study provides independent confirmation of a very similar set of experiments and results previously published by Wan et al. (2,3). Our brief but definitive study, performed as a offshoot while we were using combined liver islet isotransplantation as a model to study hepatotropic factors (4), differed only slightly from that of Wang et al. (1) as we utilized different rat strains and islet allotransplantation was via the portal vein rather than the renal subcapsular space. A closely related clinical study has also been performed (5). Surprisingly, none of this work was cited or discussed. In the early 1990s, Tzakis and Riccordi (5) working in Starzl’s laboratory reported the results of a series of combined islet and liver allografts performed in cancer patients having undergone an upper abdominal exenteration because of extensive abdominal spread. The success achieved with this series of clinical islet transplants far exceeded any results before that time and remained unparalleled for another 10 years. Their outstanding results could be logically explained in two ways. First, because the recipients were diabetic secondary to pancreatectomies, there was no autoimmune component to promote graft loss as might be expected in type 1 diabetic patients; this was the explanation invoked by most of the islet transplant community. A second possibility was that liver allografts promoted the survival of simultaneous same donor islet allografts; however, no analogous animal study had been done. Therefore, we performed a study in rats using a strain combination, Wistar-Furth (RT1u) to Lewis (RT1l), in which islet allografts were rapidly rejected [mean graft survival time was 5 days (n=6)] when embolized into the portal veins of streptozotocin-diabetic recipients and in which arterialized orthotopic liver transplants were spontaneously accepted without immunosuppression [mean graft survival time uniformly >90 days (n=10)]. When simultaneous islet/liver transplantations were performed (n=6), two rats remained normoglycemic with adequate liver function for >90 days, two normoglycemic rats died of liver allograft rejection at 13 or 30 days, and two rats became jaundiced/mildly diabetic and were killed at 41 or 63 days. In all six rats, viable islet grafts were identified histologically after death or sacrifice, indicating that in no instance had the islets rejected (2,3). These results, now confirmed by Wang et al. (1), demonstrated that simultaneous orthotopic liver transplantation protects same donor islets from allograft rejection, but that islet allografts are very immunogenic and can precipitate liver allograft rejection. The mechanistic studies by Wang et al. (1) pertaining to up-regulation of Fas ligand and T cell apoptosis are an interesting extension of this work. James R. Wright Jr.1 Weiming Yu

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