Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen
A.M. James Shapiro, M.B., B.S., Jonathan R.T. Lakey, Ph.D., Edmond A. Ryan, M.D., Gregory S. Korbutt, Ph.D., Ellen Toth, M.D., Garth L. Warnock, M.D., Norman M. Kneteman, M.D., and Ray V. Rajotte, Ph.D.
Background Registry data on patients with type 1 diabetes mellituswho undergo pancreatic islet transplantation indicate that only8 percent are free of the need for insulin therapy at one year.
Methods Seven consecutive patients with type 1 diabetes anda history of severe hypoglycemia and metabolic instability underwentislet transplantation in conjunction with a glucocorticoid-freeimmunosuppressive regimen consisting of sirolimus, tacrolimus,and daclizumab. Islets were isolated by ductal perfusion withcold, purified collagenase, digested and purified in xenoprotein-freemedium, and transplanted immediately by means of a percutaneoustranshepatic portal embolization.
Results All seven patients quickly attained sustained insulinindependence after transplantation of a mean (±SD) isletmass of 11,547±1604 islet equivalents per kilogram ofbody weight (median follow-up, 11.9 months; range, 4.4 to 14.9).All recipients required islets from two donor pancreases, andone required a third transplant from two donors to achieve sustainedinsulin independence. The mean glycosylated hemoglobin valueswere normal after transplantation in all recipients. The meanamplitude of glycemic excursions (a measure of fluctuationsin blood glucose concentrations) was significantly decreasedafter the attainment of insulin independence (from 198±32mg per deciliter [11.1±1.8 mmol per liter] before transplantationto 119±37 mg per deciliter [6.7±2.1 mmol per liter]after the first transplantation and 51±30 mg per deciliter[2.8±1.7 mmol per liter] after the attainment of insulinindependence; P<0.001). There were no further episodes ofhypoglycemic coma. Complications were minor, and there wereno significant increases in lipid concentrations during follow-up.
Conclusions Our observations in patients with type 1 diabetesindicate that islet transplantation can result in insulin independencewith excellent metabolic control when glucocorticoid-free immunosuppressionis combined with the infusion of an adequate islet mass.
Source Information
From the SurgicalMedical Research Institute and the Department of Surgery (A.M.J.S., J.R.T.L., G.S.K., G.L.W., N.M.K., R.V.R.) and the Department of Medicine (E.A.R., E.T.), University of Alberta, Edmonton, Alta., Canada.
Address reprint requests to Dr. Shapiro at 2D4.37 Department of Surgery, University of Alberta Hospitals, Mackenzie Health Sciences Center, 8440 112 St., Edmonton, AB T6G 2B7, Canada, or at amjs{at}powersurfr.com.
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(2005). Human Cord Blood-Derived Cells Generate Insulin-Producing Cells In Vivo. Stem Cells
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Herrington, J., Sanchez, M., Wunderler, D., Yan, L., Bugianesi, R. M, Dick, I. E, Clark, S. A, Brochu, R. M, Priest, B. T, Kohler, M. G, McManus, O. B
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Nyqvist, D., Mattsson, G., Kohler, M., Lev-Ram, V., Andersson, A., Carlsson, P.-O., Nordin, A., Berggren, P.-O., Jansson, L.
(2005). Pancreatic islet function in a transgenic mouse expressing fluorescent protein. J Endocrinol
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Soria, B., Bedoya, F. J., Martin, F.
(2005). Gastrointestinal Stem Cells I. Pancreatic stem cells. Am. J. Physiol. Gastrointest. Liver Physiol.
289: G177-G180
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Dombrowski, F., Jost, C. M., Manekeller, S., Evert, M.
(2005). Cocarcinogenic Effects of Islet Hormones and N-Nitrosomorpholine in Hepatocarcinogenesis after Intrahepatic Transplantation of Pancreatic Islets in Streptozotocin-Diabetic Rats. Cancer Res.
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Warnock, G. L., Meloche, R. M., Thompson, D., Shapiro, R. J., Fung, M., Ao, Z., Ho, S., He, Z., Dai, L.-J., Young, L., Blackburn, L., Kozak, S., Kim, P. T. W., Al-Adra, D., Johnson, J. D., Liao, Y.-H. T., Elliott, T., Verchere, C. B.
(2005). Improved Human Pancreatic Islet Isolation for a Prospective Cohort Study of Islet Transplantation vs Best Medical Therapy in Type 1 Diabetes Mellitus. Arch Surg
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Nyqvist, D., Kohler, M., Wahlstedt, H., Berggren, P.-O.
(2005). Donor Islet Endothelial Cells Participate in Formation of Functional Vessels Within Pancreatic Islet Grafts. Diabetes
54: 2287-2293
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Jacobson, P. A., Green, K. G., Hering, B. J.
(2005). Mycophenolate Mofetil in Islet Cell Transplant: Variable Pharmacokinetics but Good Correlation Between Total and Unbound Concentrations. J Clin Pharmacol
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Billotey, C., Aspord, C., Beuf, O., Piaggio, E., Gazeau, F., Janier, M. F., Thivolet, C.
(2005). T-Cell Homing to the Pancreas in Autoimmune Mouse Models of Diabetes: In Vivo MR Imaging. Radiology
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Asfari, M, Berta, S, Coffy, S, Kergoat, M, Charon, C, Audet, A
(2005). Short-term treatment with mycophenolic acid and tacrolimus is tolerogenic for INS-1 cell clone transplantation and the deleterious effects of the drugs are limited: in vivo and in vitro studies. J Endocrinol
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Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R.T., Shapiro, A.M. J.
(2005). Five-Year Follow-Up After Clinical Islet Transplantation. Diabetes
54: 2060-2069
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Mysore, T. B., Shinkel, T. A., Collins, J., Salvaris, E. J., Fisicaro, N., Murray-Segal, L. J., Johnson, L. E.A., Lepore, D. A., Walters, S. N., Stokes, R., Chandra, A. P., O'Connell, P. J., d'Apice, A. J.F., Cowan, P. J.
(2005). Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function. Diabetes
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Wang, W., Upshaw, L., Strong, D M., Robertson, R P., Reems, J.
(2005). Increased oxygen consumption rates in response to high glucose detected by a novel oxygen biosensor system in non-human primate and human islets. J Endocrinol
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BABAYA, N., NAKAYAMA, M., EISENBARTH, G. S.
(2005). The Stages of Type 1A Diabetes. Ann. N. Y. Acad. Sci.
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Fiorina, P., Venturini, M., Folli, F., Losio, C., Maffi, P., Placidi, C., La Rosa, S., Orsenigo, E., Socci, C., Capella, C., Del Maschio, A., Secchi, A.
(2005). Natural History of Kidney Graft Survival, Hypertrophy, and Vascular Function in End-Stage Renal Disease Type 1 Diabetic Kidney-Transplanted Patients: Beneficial impact of pancreas and successful islet cotransplantation. Diabetes Care
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Suarez-Pinzon, W. L., Lakey, J. R. T., Brand, S. J., Rabinovitch, A.
(2005). Combination Therapy with Epidermal Growth Factor and Gastrin Induces Neogenesis of Human Islet {beta}-Cells from Pancreatic Duct Cells and an Increase in Functional {beta}-Cell Mass. J. Clin. Endocrinol. Metab.
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Rao, P., Roccisana, J., Takane, K. K., Bottino, R., Zhao, A., Trucco, M., Garcia-Ocana, A.
(2005). Gene Transfer of Constitutively Active Akt Markedly Improves Human Islet Transplant Outcomes in Diabetic Severe Combined Immunodeficient Mice. Diabetes
54: 1664-1675
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Johansson, H., Lukinius, A., Moberg, L., Lundgren, T., Berne, C., Foss, A., Felldin, M., Kallen, R., Salmela, K., Tibell, A., Tufveson, G., Ekdahl, K. N., Elgue, G., Korsgren, O., Nilsson, B.
(2005). Tissue Factor Produced by the Endocrine Cells of the Islets of Langerhans Is Associated With a Negative Outcome of Clinical Islet Transplantation. Diabetes
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