Safety and Viability of MicroencapsulatedHuman Islets Transplanted Into DiabeticHumansBERNARD E. TUCH,FRACP, PHD1,2GREGORY W. KEOGH,FRACS3LINDY J. WILLIAMS,BSC2WEI WU,PHD2JAYNE L. FOSTER,PHD2VIJAYGANAPATHY VAITHILINGAM,MSC2ROBERT PHILIPS,FRANZCR4OBJECTIVE — Transplantation of insulin-producing cells placed inside microcapsules isbeing trialled to overcome the need for immunosuppressive therapy.RESEARCH DESIGN AND METHODS — Four type 1 diabetic patients with no de-tectable C-peptide received an intraperitoneal infusion of islets inside microcapsules of bariumalginate (mean 178,200 islet equivalents on each of eight occasions).RESULTS — C-peptide was detected on day 1 post-transplantation, and blood glucose levelsand insulin requirements decreased. C-peptide was undetectable by 1– 4 weeks. In a multi-isletrecipient, C-peptide was detected at 6 weeks after the third infusion and remains detectable at2.5 years. Neither insulin requirements nor glycemic control was affected. Capsules recovered at16 months were surrounded by fibrous tissue and contained necrotic islets. No major side effectsor infection occurred.CONCLUSIONS — While allografting of encapsulated human islets is safe, efficacy of thecells needs to improve for the therapy to make an impact on the clinical scene.Diabetes Care 32:1887–1889, 2009Transplantation of insulin-producingcells placed inside capsules is a strat-egy that is being trialled to overcomethe need for immunosuppressive ther-apy in insulin-dependent diabetic peo-ple (1). We have made microcapsules ofbarium alginate and shown that insulin-producing porcine cells can function asefficiently inside such capsules as whennonencapsulated (2). Moreover, humanislets placed in these capsules normalizeblood glucose levels when engrafted indiabetic mice (3,4). In the currentstudy, we transplanted four type 1 dia-betic humans with encapsulated humanislets.RESEARCH DESIGN ANDMETHODS — Cadaver pancreata wereobtained with consent, and islets were iso-lated by digestion with collagenase NB1premium grade and neutral protease NB(Serva, Germany). Islets were placed inbarium alginate microcapsules (2), andtheir median average diameter from eightislet preparations was 340 m (range255–750).Median viability of the encapsulatedislets, assessed with the fluorescent dyescarboxyfluorescein diacetate and pro-pidium iodide (2), was 73% (range 60 –80%). Purity was 68% (range 50 – 88%),and insulin content (2) was 1.1 mU/isletequivalents (IEQs) (range 0.1–35). Themedian stimulation index of the islets ex-posed to 20 mmol/l glucose, comparedwith 2.8 mmol/l glucose, for 1 h was 1.22(range 1.0 –2.4). The median number ofIEQs transplanted on each occasion was178,200 (range 98,200 –227,900). Con-ditioned culture medium was free of mi-crobial contamination.Of the 14 diabetic people screened forphase 1 of the clinical trial, 7 were selectedand 4 were transplanted over a period of 19months. The seven with long-standing type1 diabetes had no endogenous insulin pro-duction (no C-peptide in serum during anarginine tolerance test and none in 24-hurine), BMI ⬍25 kg/m2, and weight ⬍70kg. Those transplanted had antibodies toneither GAD nor islet cell surface antigens(ICA512). One person received four isletinfusions over 7 months with three in the1st month; a second received two infu-sions 10 months apart; and the other tworecipients received one infusion each (seeTables A1 and A2 in the online appendixavailable at http://care.diabetesjournals.org/cgi/content/full/dc09-0744/DC1). Infu-sions were carried out on an outpatientbasis in the Department of Medical Imag-ing, Prince of Wales Hospital, Sydney,Australia.No immunosuppression was used,but recipients did take both a mild anti-inflammatory agent (Atorvastatin 20 mg)and antioxidants (vitamin A 50,000 units,vitamin B6 100 mg, and vitamin E 750units) after each transplant. For the lasttwo islet infusions, exenatide 5 g b.i.d.was administered in an attempt to en-hance -cell survival and function.Approval for all the procedures per-formed was obtained from the InstitutionalHuman Research Ethics Committee.RESULTS — C-peptide was detectedin urine on the 1st day after the islet infu-sion (median 0.59 nmol/l [range 0.11–1.79]; 0.15 nmol/mmol creatinine [range0.06– 0.25]) with levels declining there-after and becoming undetectable at 1–4weeks (median 10 days) later. Both bloodglucose levels and insulin requirementswere also lower on the 1st day after trans-plantation by an average (means ⫾ SEM)●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●From the1Australian Foundation for Diabetes Research, Sydney, Australia; the2Diabetes Transplant Unit,Prince of Wales Hospital, Sydney, Australia; the3Department of Surgery, Prince of Wales Hospital, SydneyAustralia; and the4Department of Medical Imaging, Prince of Wales Hospital, Sydney, Australia.Corresponding author: Bernard Tuch, [email protected] 20 April 2009 and accepted 15 June 2009.Published ahead of print at http://care.diabetesjournals.org on 23 June 2009. DOI: 10.2337/dc09-0744.Clinical trial reg. no. ACTRN12609000192280 (Australian and New Zealand Clinical Trials Registry).© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properlycited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.Emerging Treatments and TechnologiesBRIEF REPORTcare.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 1887of 36 ⫾ 8% and 22 ⫾ 3%, respectively,but not thereafter. An arginine tolerancetest was carried out on the 7th day, andplasma C-peptide was undetectable.In the recipient of the four islet infu-sions, urinary C-peptide was detected at 6weeks after the third infusion and continuesto remain detectable at 2.5 years. C-peptidelevels are 0.06 –0.34 nmol/l or 0.02–0.06nmol/mmol creatinine. The small amountof insulin being produced did not alter in-sulin requirements or glycemic control.To better understand what was occur-ring in the transplanted capsules, a lapa-roscopy was performed
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