Pravastatin Improves Glucose Regulation and Biocompatibility of Agarose Encapsulated Porcine Islets Following Transplantation Into Pancreatectomized Dogs Lawrence S

Florida International University FIU Digital Commons All Faculty 5-19-2014 Pravastatin Improves Glucose Regulation and Biocompatibility of Agarose Encapsulated Porcine Islets following Transplantation into Pancreatectomized Dogs Lawrence S. Gazda The Rogosin Institute-Xenia Division Horatiu V. Vinerean Florida International University, [email protected] Melissa A. Laramore The Rogosin Institute-Xenia Division Richard D. Hall Bob Evans Farms Joseph W. Carraway NAMSA See next page for additional authors Follow this and additional works at: https://digitalcommons.fiu.edu/all_faculty Recommended Citation Gazda, Lawrence S.; Vinerean, Horatiu V.; Laramore, Melissa A.; Hall, Richard D.; Carraway, Joseph W.; and Smith, Barry H., "Pravastatin Improves Glucose Regulation and Biocompatibility of Agarose Encapsulated Porcine Islets following Transplantation into Pancreatectomized Dogs" (2014). All Faculty. 52. https://digitalcommons.fiu.edu/all_faculty/52 This work is brought to you for free and open access by FIU Digital Commons. It has been accepted for inclusion in All Faculty by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. Authors Lawrence S. Gazda, Horatiu V. Vinerean, Melissa A. Laramore, Richard D. Hall, Joseph W. Carraway, and Barry H. Smith This article is available at FIU Digital Commons: https://digitalcommons.fiu.edu/all_faculty/52 Hindawi Publishing Corporation Journal of Diabetes Research Volume 2014, Article ID 405362, 10 pages http://dx.doi.org/10.1155/2014/405362 Research Article Pravastatin Improves Glucose Regulation and Biocompatibility of Agarose Encapsulated Porcine Islets following Transplantation into Pancreatectomized Dogs Lawrence S. Gazda,1,2 Horatiu V. Vinerean,3 Melissa A. Laramore,1 Richard D. Hall,4 Joseph W. Carraway,5 and Barry H. Smith2,6 1 The Rogosin Institute-Xenia Division, 740 Birch Road, Xenia, OH 45385, USA 2 The Rogosin Institute, New York, NY 10021, USA 3 Florida International University, Miami, FL 33199, USA 4 BobEvansFarms,Inc.,NewAlbany,OH43054,USA 5 NAMSA, Northwood, OH 43619, USA 6 NewYork-Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY 10021, USA Correspondence should be addressed to Lawrence S. Gazda; [email protected] Received 3 February 2014; Revised 6 May 2014; Accepted 7 May 2014; Published 19 May 2014 Academic Editor: Hiroshi Okamoto Copyright © 2014 Lawrence S. Gazda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The encapsulation of porcine islets is an attractive methodology for the treatment of Type I diabetes. In the current study, the use of pravastatin as a mild anti-inflammatory agent was investigated in pancreatectomized diabetic canines transplanted with porcine islets encapsulated in agarose-agarose macrobeads and given 80 mg/day of pravastatin (=3) while control animals did not receive pravastatin (=3). Control animals reached preimplant insulin requirements on days 18, 19, and 32. Pravastatin- treated animals reached preimplant insulin requirements on days 22, 27, and 50. Two animals from each group received a second macrobead implant: control animals remained insulin-free for 15 and 21 days (AUC = 3003 and 5078 mg/dL/24 hr days 1 to 15) and reached preimplant insulin requirements on days 62 and 131. Pravastatin treated animals remained insulin-free for 21 and 34 days (AUC = 1559 and 1903 mg/dL/24 hr days 1 to 15) and reached preimplant insulin requirements on days 38 and 192. Total incidence (83.3% versus 64.3%) and total severity (22.7 versus 18.3) of inflammation on tissue surfaces were higher in the control group at necropsy. These findings support pravastatin therapy in conjunction with the transplantation of encapsulated xenogeneic islets for the treatment of diabetes mellitus. 1. Introduction membrane should allow the diffusion of insulin and other peptides out of the encapsulation device while still permitting Type 1 diabetic patients face a lifetime of daily insulin nutrient exchange to support the islet cells. injections due to destruction of the insulin-producing islets FollowingtheseminalstudiesofLimandSun[1]in of Langerhans within the pancreas. Alternatively, whole whichencapsulatedratisletswereshowntorestorenormo- pancreas or the islets alone, after isolation from the pan- glycemia in diabetic rats, many groups have attempted islet creas, can be transplanted to the patient. Transplantation of grafting using large animal models as a prelude to clinical either the pancreas or the islets, however, requires a lifetime trials. Warnock and Rajotte demonstrated the applicability of immunosuppressive therapy. One possible solution to of nonencapsulated islet transplantation in dogs with long- avoid lifelong immunosuppression is to encapsulate the islets term function of islets autografted to either the spleen or within a semipermeable membrane. The rationale behind this liver [2]. Allogeneic islet transplantation within intravascular strategy is to protect the islets from destruction by immune devices has also been successful. Sullivan et al. reported 6 cells and immune mediators such as cytokines. The porous of 10 pancreatectomized dogs without exogenous insulin for 2 Journal of Diabetes Research up to 5 months following the grafting of such devices seeded steel cages, 32 W × 42 L × 32 H, with rubbercoated mesh with allogeneic islets [3]. Brunetti et al. used an intravas- flooring and a stainless steel platform, 32 × 40 . Science Diet culardevicetoatleastpartiallyreversehyperglycemiain Growth (Hill’s, 6730) was given to the animals twice daily. spontaneously diabetic dogs grafted with xenogeneic porcine Clean municipal water was provided ad libitum.Viokase islets [4]. A similar intravascular device study in pancreate- (Henry Schein, 9758341) powder was added to food at a dose ctomized dogs that received porcine islets was reported by of 1 tsp/meal following pancreatectomy. The temperature ∘ Makietal.inwhich7of17dogsweremaintainedonreduced of the room was maintained within 18–28 Cwithrelative insulin requirements for 53–114 days while 2 animals received humidity of 30–70%. A 12 hour light cycle was maintained reducedinsulinfor218and263days[5]. Thrombosis of the throughout the study with lights on at 0700 hours. All study vascular shunt, however, remains an ongoing concern for protocol procedures were approved by The Rogosin Institute such devices. Animal Care and Use Committee (IACUC). The Rogosin To avoid such complications associated with intravas- Institute-Xenia Division animal facility holds Full Accred- cular devices and to limit immunosuppression, many itation status awarded by the Association for Assessment researchers have turned to transplanting encapsulated islets and Accreditation of Laboratory Animal Care, International into the peritoneal cavity as free-floating diffusion structures. (AAALAC, Int.). Soon-Shiong et al. demonstrated 63–172 days of insulin- independence with allogeneic islets microencapsulated in 2.2. Isolation of Porcine Islets and Production of Porcine Islet alginate and transplanted into the peritoneal cavity of spon- Macrobeads. Donor islets were prepared from Newsham taneously diabetic dogs receiving subtherapeutic doses of sows over two years of age and with multiple parities. After cyclosporine [6]. Similarly, reduced insulin requirements electrical stun and exsanguination (Bob Evans Farms, Xenia, and/or insulin independence was reported by Lanza et OH), pancreata were retrieved and transported to the islet al. using XM-50 tubular membranes in the absence of isolation laboratory in cold Hank’s Balanced Salt Solution immunosuppression [7]. This group later reported insulin- (HBSS; Mediatech, 21-020) on ice. Warm ischemia times independence for 60 to >175 days in 4 spontaneously diabetic averaged 14.43 minutes while cold ischemia times ranged dogs using alginate encapsulated canine islets on low-dose from 30 minutes to one hour. Islet isolation was carried cyclosporine therapy [8]. More recently, Wang et al. were able out as previously described [14]. Briefly, after trimming the to discontinue exogenous insulin therapy in 8 of 9 pancre- gland of fat and connective tissue, the main pancreatic atectomized canines for 64–106 days and in one animal for duct was cannulated and injected with HBSS containing 214 days using allogeneic islets encapsulated in a triple mem- collagenase V (Sigma Aldrich, C9263) at a concentration brane alginate-based bead without any immunosuppression of 1.8 g/L, and protamine (Sigma Aldrich, P4005) at a or anti-inflammatory treatment9 [ ]. Kin et al. demonstrated concentration of 0.06 g/L. Four times the gram weight of insulin independence for 6–119 days in pancreatectomized thepancreas(inmL)wasperfusedthroughthepancreatic dogs receiving xenogeneic porcine islets encapsulated in ∘ duct at a rate of 150 mL/min at 18 C. Islets were purified agarose and polystyrene sulfonic acid [10]. A bioartificial on discontinuous Eurocollins (Mediatech, 99-408)—Ficoll endocrine pancreas consisting of porcine islets contained in 3 (Sigma Aldrich, F9378) gradients of densities 1.105 g/cm , an agarose matrix within semipermeable membranes was 3 3 1.095 g/cm ,and1.055g/cm in 50 mL polystyrene conical also shown to reduce insulin requirements in pancreatec- tubes. The tubes were centrifuged at 2000 RPM, and islet- tomized dogs for up to 17 weeks [11]. containing

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