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Vascularized Islet Cell Transplantation in Miniature Swine Islet-Kidney Allografts Correct the Diabetic Hyperglycemia Induced by Total Pancreatectomy Naoki Kumagai 1 , John C. LaMattina 1 , Chisako Kamano 1 , Parsia A. Vagefi 1 , Rolf N. Barth 1 , John J. O’Neil 2 , Shin Yamamoto 1 , Shannon G. Moran 1 , Ryu Utsugi 3 , David H. Sachs 1 and Kazuhiko Yamada 1 1 Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts 3 Department of Urology, Niigata University School of Medicine, Niigata, Japan Abstract We have previously reported the preparation of vascularized islet-kidneys (IKs) by transplantation of islets under the autologous kidney capsule. Here, we compare the efficacy of transplanting vascularized versus nonvascularized islets into diabetic allogeneic swine recipients. In the vascularized islet transplantation (5,000 islet equivalents [IE]/kg), recipients received minor-mismatched ( n = 4) or fully-mismatched ( n = 2) IKs after pancreatectomy, with a 12-day course of cyclosporine A (CyA) or FK506, respectively. For the nonvascularized islet transplantation (7,000 IE/kg), three recipients received minor-mismatched islets alone and two recipients received minor-mismatched donor islets placed in a donor kidney on the day of transplantation. All recipients of nonvascularized islets were treated with a 12-day course of CyA. With vascularized islet transplantation, pancreatectomized recipients were markedly hyperglycemic pretransplant (fasting blood glucose >300 mg/dl). After composite IK transplantation, all recipients developed and maintained normoglycemia (<120 mg/dl) and stable renal function indefinitely (>3 months), and insulin therapy was not required. Major histocompatibility complex-mismatched recipients demonstrated in vitro donor-specific unresponsiveness. In contrast, recipients of nonvascularized islets remained hyperglycemic. In conclusion, IK allografts cured surgically induced diabetes across allogeneic barriers, whereas nonvascularized islet transplants did not. These data indicate that prevascularization of islet allografts is crucial for their subsequent engraftment and that composite IKs may provide a strategy for successful islet transplantation. Footnotes Address correspondence and reprint requests to Kazuhiko Yamada, MD, PhD, Transplantation Biology Research Center, Massachusetts General Hospital, MGH-East, Building 149-9019, 13th St., Boston, MA 02129. E-mail: kaz.yamada{at}tbrc.mgh.harvard.edu . Received for publication 8 April 2002 and accepted in revised form 8 August 2002. CML, cell-mediated lymphocytotoxicity; CyA, cyclosporine A; FBG, fasting blood glucose; H&E, hematoxylin and eosin; HBSS, Hank’s balanced salt solution; IE, islet equivalents; IK, islet-kidney; MHC, major histocompatibility complex; MLR, mixed lymphocyte response; PBMC, peripheral blood mononuclear cells; POD, postoperative day. DIABETES

The annual rate of kidney graft loss caused by chronic allograft nephropathy (CAN) has not improved over the past decade. Recent reports suggest that acute renal ischemia results in development of CAN. The goal of the present study was to assess the renoprotective potential and safety of hepatocyte growth factor (HGF) gene transfer using a porcine kidney transplant warm ischemia injury model. Following left porcine kidney removal, 10 min of warm ischemic injury was intentionally induced. Next, the HGF expression vector or vehicle was infused into the renal artery with the renal vein clamped ex vivo , and electric pulses were discharged using bathtub-type electrodes. Kidney grafts were then transplanted after removing the right kidney. Histopathological examination of vehicle-transfected kidney transplant revealed initial tubular injury followed by tubulointerstitial fibrosis. In contrast, HGF-transfected kidneys showed no initial tubular damage and no interstitial fibrosis at 6 months post-transplant. We conclude that electroporation-mediated ex vivo HGF gene transfection protects the kidney against graft injury in a porcine model.

We have previously reported the preparation of vascularized islet-kidneys (IKs) by transplantation of islets under the autologous kidney capsule. Here, we compare the efficacy of transplanting vascularized versus nonvascularized islets into diabetic allogeneic swine recipients. In the vascularized islet transplantation (5,000 islet equivalents [IE]/kg), recipients received minor-mismatched (n = 4) or fully-mismatched (n = 2) IKs after pancreatectomy, with a 12-day course of cyclosporine A (CyA) or FK506, respectively. For the nonvascularized islet transplantation (7,000 IE/kg), three recipients received minor-mismatched islets alone and two recipients received minor-mismatched donor islets placed in a donor kidney on the day of transplantation. All recipients of nonvascularized islets were treated with a 12-day course of CyA. With vascularized islet transplantation, pancreatectomized recipients were markedly hyperglycemic pretransplant (fasting blood glucose >300 mg/dl). After composite IK transplantation, all recipients developed and maintained normoglycemia (<120 mg/dl) and stable renal function indefinitely (>3 months), and insulin therapy was not required. Major histocompatibility complex-mismatched recipients demonstrated in vitro donor-specific unresponsiveness. In contrast, recipients of nonvascularized islets remained hyperglycemic. In conclusion, IK allografts cured surgically induced diabetes across allogeneic barriers, whereas nonvascularized islet transplants did not. These data indicate that prevascularization of islet allografts is crucial for their subsequent engraftment and that composite IKs may provide a strategy for successful islet transplantation.