P-5：The approaches to Overcome Islet Graft Failure

Jyuhn-Huarng Juang, Chien-Hung Kuo, Wen-Tsong Lu, Brend Ray-Sea

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Memorial Hospital, Taoyuan, Taiwan, R.O.C.

Islet transplantation offers a physiological approach for precise restoration of glucose homeostasis, thereby reversing the metabolic and neurovascular complications of diabetes. In the past, there were only a few early successes with human islet transplantation and the initial results were very disappointing. However, recent reports of great success have renewed interest in islet transplantation as a possible therapeutic option for patients with diabetes. Even though the insulin requirement decreased after the first transplant, it was after repeat transplant(s) that patients became free from insulin therapy. The reasons for islet allograft failure may include both nonimmunological (insufficient b-cell mass and problems related to islet engraftment) and immunological (immune rejection, toxicity of immunosuppressants and autoimmune recurrence) factors.

To improve the outcome of islet transplantation, we have been focusing on three directions to improve the outcome of islet transplantation. The shortage of human donor pancreata has led to our efforts to expand the human donor pool by using old donors, cryopreserved islets, and neonatal porcine pancreatic cell clusters. To solve the problems of islet engraftment, we treated recipients during the peritransplant period with additional islets, exogenous insulin, hyperbaric oxygen, pentoxyphylline, 15-deoxyspergualin and nordihydroguaiaretic acid. They all showed beneficial for the islet grafts and transplantation results. In contrast, islet culture with vascular endothelial growth factor before transplantation did not increase graft vasculature, and posttranaplant administration of gliclazide to the recipients did not enhance graft function. Immunoisolation of donor cells have been used to overcome immunological problems. We found transplantation of encapsulated islets in combination with administration of 15-deoxyspergualine attenuated pericapsular cellular infiltration and prolong the graft survival; and IL-1 receptor antagonist protected encapsuled islets against the suppressive effects of IL-1b. In terms of tolerance induction, we transplanted adenoviral vectors carrying CTLA4-Ig to prolong islet xenografts, and DCR 3 transgenic islet to prevent autoimmune destruction. However, FasL transgenic islets could not protect allografts from rejection.

In conclusion, islet transplantation would become a routine treatment in clinical practice once more islet sources and safer forms of immunosuppression could be obtained.