The Experts below are selected from a list of 1041 Experts worldwide ranked by ideXlab platform
Jonathan R T Lakey - One of the best experts on this subject based on the ideXlab platform.
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Short-term storage of the ischemically damaged human pancreas by the two-layer method prior to islet isolation.
Cell Transplantation, 2020Co-Authors: Toshiaki Tsujimura, Thomas A Churchill, Jose G Avila, Yoshikazu Kuroda, A. M. James Shapiro, Jonathan R T LakeyAbstract:A two-layer cold storage method (TLM) allows sufficient oxygen delivery to pancreata during preservation and resuscitates the viability of ischemically damaged pancreata in the canine pancreas transplant model. In this study, we applied a short-term preservation of the TLM to human pancreata after prolonged cold ischemia prior to islet isolation, and investigated the mechanisms of resuscitation of the ischemically damaged human pancreas by the TLM. Human pancreata were procured from cadaveric donors and preserved by the TLM for 3.2 ± 0.5 h after 11.1 ± 0.9 h of cold storage in UW (TLM group), or by cold UW alone for 11.0 ± 0.3 h (UW group). Islet isolations of all pancreata were performed using the Edmonton Protocol. Islet recovery and in vitro functional viability of isolated islets were significantly increased in the TLM group compared with the UW group. According to the criteria of the Edmonton Protocol, 10/14 cases (71%) in the TLM group were transplanted to patients with type I diabetes mellitus comp...
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Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials
Challenges in Pancreatic Pathology, 2017Co-Authors: Michael Alexander, Shiri Li, Huy Nguyen, Antonio Flores, Elliot T. Botvinick, Jonathan R T LakeyAbstract:Islet transplantation, with the advent of the Edmonton Protocol in 2000, has offered a significant alternative for long-lasting treatment of type 1 diabetes. However, the immunosuppression required for transplantation has the cytotoxic effect on pancreatic islets, and thus limiting the long-term efficacy of the transplant. Immediate loss of islets after transplant was also observed because of immediate blood-mediated inflammatory response (IBMIR), which kills islets transplanted in the liver through portal vein. There is also commonly a lack of microvascular blood supply to the transplanted islets. In this chapter, we will review the variety of technologies used to protect transplanted islets against toxicity of immunosuppression, immune rejection, and inflammatory response. We will evaluate the mechanisms of these technologies and their progress in solving the challenges to islet transplantation. The technologies include encapsulation of transplanted islets in various polymers, transplants in sites other than the liver, and creation of new prevascularized transplant site. These technologies offer several mechanisms to prevent immune rejection or immediate contact with cytotoxic inflammatory response, in addition to maintaining islet integrity. New transplant sites are also being developed to support the islets, by allowing establishment of microvasculature and innervation, prior to addition of the islets.
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human islet mass morphology and survival after cryopreservation using the Edmonton Protocol
Islets, 2013Co-Authors: Priya Miranda, A James M Shapiro, Viswanathan Mohan, Sekhar Ganthimathy, Ranjit Mohan Anjana, S Gunasekaran, Venkatachalam Thiagarajan, Thomas A Churchill, Jonathan R T LakeyAbstract:The aim of this study was to assess recovery, cell death, and cell composition of post-thaw cultured human islets. Cryopreserved islets were provided by the Clinical Islet Transplant Program, Edmonton, Canada. Islets were processed using media prepared in accordance with Pre-Edmonton and Edmonton Protocols. Cryopreserved islets were rapidly thawed and cultured for 24 h, 3 d, 5 d, and 7 d, following which they were processed for histology. Islet quantification, integrity, morphology and tissue turnover were studied via hematoxylin and eosin stained sections. Ultrastructure was studied by electron microscopy and endocrine cell composition by immunohistochemistry. Using the Pre-Edmonton Protocol, islet recovery was 50.1% and islet survival was 50% at 24 h while for the Edmonton Protocol, the islet recovery was 69.4% (p < 0.001) and islet survival, 50% at ≈2.5 d. With an increasing culture duration although the physical integrity was retained there was an increasing loss of cohesivity both at light microscopic and at ultrastructure level regardless of the Protocols used. Percentage islet survival and tissue turnover correlated negatively with culture duration in both Protocols. The Edmonton Protocol appears to preserve the islets better. However, culture duration adversely affects islet survival and quality, indicating the need for more optimal cryopreservation and culture techniques.
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The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells
Diabetologia, 2006Co-Authors: C. T. Bussiere, Jonathan R T Lakey, A M J Shapiro, Gregory S KorbuttAbstract:Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this Protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue.
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XIAP Overexpression in Human Islets Prevents Early Posttransplant Apoptosis and Reduces the Islet Mass Needed to Treat Diabetes
Diabetes, 2005Co-Authors: Juliet Emamaullee, Jonathan R T Lakey, Ray V Rajotte, A. M. James Shapiro, Peter Liston, Robert G. Korneluk, John F ElliottAbstract:The Edmonton Protocol for treatment of type 1 diabetes requires islets from two or more donors to achieve euglycemia in a single recipient, primarily because soon after portal infusion, the majority of the transplanted cells undergo apoptosis due to hypoxia and hypoxia reperfusion injury. X-linked inhibitor of apoptosis protein (XIAP) is a potent endogenous inhibitor of apoptosis that is capable of blocking the activation of multiple downstream caspases, and XIAP overexpression has previously been shown to enhance engraftment of a murine β-cell line. In this study, human islets transduced with a XIAP-expressing recombinant adenovirus were resistant to apoptosis and functionally recovered following in vitro stresses of hypoxia and hypoxia with reoxygenation (models reperfusion injury). Furthermore Ad-XIAP transduction dramatically reduced the number of human islets required to reverse hyperglycemia in chemically diabetic immunodeficient mice. These results suggest that by transiently overexpressing XIAP in the immediate posttransplant period, human islets from a single donor might be used to effectively treat two diabetic recipients.
Shinichi Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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Temporal Decline in Sirolimus Elimination Immediately After Pancreatic Islet Transplantation
Drug Metabolism and Pharmacokinetics, 2020Co-Authors: Eriko Sato, Shinichi Matsumoto, Teru Okitsu, Masahiro Shimomura, Ikuko Yano, Hirofumi Noguchi, Yasuhiro Iwanaga, Satohiro Masuda, Toshiya Katsura, Hideo NagataAbstract:Summary: Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton Protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.
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Comparison of modified Celsior solution and M-kyoto solution for pancreas preservation in human islet isolation.
Cell Transplantation, 2010Co-Authors: Hirofumi Noguchi, Naoya Kobayashi, Bashoo Naziruddin, Nicholas Onaca, Andrew Jackson, Masayuki Shimoda, Tetsuya Ikemoto, Yasutaka Fujita, Marlon F. Levy, Shinichi MatsumotoAbstract:Since the successful demonstration of the Edmonton Protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas preservation systems. In this study, we ...
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Seven consecutive successful clinical islet isolations with pancreatic ductal injection.
Cell Transplantation, 2009Co-Authors: Shinichi Matsumoto, Bashoo Naziruddin, Andrew Jackson, Masayuki Shimoda, Tetsuya Ikemoto, Yasutaka Fujita, Yoshiko Tamura, Hirofumi Noguichi, Greg Olson, Daisuke ChujoAbstract:Inconsistent islet isolation is one of the issues of clinical islet transplantation. In the current study, we applied ductal injection to improve the consistency of islet isolation. Seven islet isolations were performed with the ductal injection of ET-Kyoto solution (DI group) and eight islet isolations were performed without the ductal injection (standard group) using brain-dead donor pancreata. Isolated islets were evaluated based on the Edmonton Protocol for transplantation. The DI group had significantly higher islet yields (588,566 +/- 64,319 vs. 354,836 +/- 89,649 IE, p < 0.01) and viability (97.3 +/- 1.2% vs. 92.6 +/- 1.2%, p < 0.02) compared with the standard group. All seven isolated islet preparations in the DI group (100%), versus only three out of eight isolated islet preparations (38%) in the standard group met transplantation criteria. The islets from the DI group were transplanted into three type 1 diabetic patients and all three patients became insulin independent. Ductal injection significantly improved quantity and quality of isolated islets and resulted in high success rate of clinical islet transplantation. This simple modification will reduce the risk of failure of clinical islet isolation.
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Islet transplantation at the Diabetes Research Institute Japan
Journal of Hepato-biliary-pancreatic Surgery, 2008Co-Authors: Hirofumi Noguchi, Shinichi MatsumotoAbstract:Since the Edmonton Protocol was announced, more than 600 patients with type 1 diabetes at more than 50 institutions have received islet transplantation to treat their disease. We recently established a new islet isolation Protocol, called the Kyoto Islet Isolation Method, based on the Ricordi method. It includes an in-situ cooling system for pancreas procurement, pancreatic ductal protection, a modified two-layer (M-Kyoto /perfluorochemical [PFC]) method of pancreas preservation, and a new islet purification solution (Iodixanol-based solution). Using this islet isolation method, we isolated islets from 19 human pancreata of non-heart-beating donors and transplanted 16 preparations into seven patients with type 1 diabetes between April 7, 2004 and November 18, 2005. The percentage of those meeting the release criteria of the Edmonton Protocol was more than 80%. We also performed living-donor transplantation of islets for unstable diabetes on January 19, 2005. Establishment of this method enables us to make diabetic patients insulin-independent, using islets not only from two or three pancreata of non-heart-beating donors but also using islets from half a pancreas from a living donor.
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Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor
Diabetologia, 2007Co-Authors: Hirofumi Noguchi, Yusuke Nakai, Michiko Ueda, Yumi Masui, Shiroh Futaki, N. Kobayashi, Shuji Hayashi, Shinichi MatsumotoAbstract:Aims/hypothesis Although application of the Edmonton Protocol has markedly improved the outcome for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has remained low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. The aim of this study was to map the c-Jun NH2-terminal kinase (JNK) pathway that mediates islet loss during islet transplantation and to clarify whether intraportal injection with JNK inhibitor during islet transplantation can prevent islet graft loss.
Camillo Ricordi - One of the best experts on this subject based on the ideXlab platform.
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Islet transplantation with alemtuzumab induction and calcineurin-free maintenance immunosuppression results in improved short- and long-term outcomes.
Transplantation, 2008Co-Authors: Tatiana Froud, Camillo Ricordi, Norma S. Kenyon, David Baidal, Raquel N. Faradji, Pablo Cure, Davide Mineo, Gennaro Selvaggi, Rodolfo AlejandroAbstract:BACKGROUND: Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton Protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes. MATERIALS AND METHODS: Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton Protocol. RESULTS: Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P
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international trial of the Edmonton Protocol for islet transplantation
The New England Journal of Medicine, 2006Co-Authors: A James M Shapiro, Antonio Secchi, Camillo Ricordi, Bernhard J Hering, Hugh Auchincloss, Robert Lindblad, Paul R Robertson, M D Brendel, Thierry Berney, Daniel C BrennanAbstract:Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common Protocol (the Edmonton Protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton Protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)
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pancreatic islet transplantation for treating diabetes
Expert Opinion on Biological Therapy, 2006Co-Authors: Shinichi Matsumoto, Yukihide Yonekawa, Teru Okitsu, Hideo Nagata, Naoya Kobayashi, Hirofumi Noguchi, Yasuhiro Iwanaga, Camillo RicordiAbstract:Pancreatic islet transplantation is one of the options for treating diabetes and has been shown to improve the quality of life of severe diabetic patients. Since the Edmonton Protocol was announced, islet transplantation have advanced considerably, including islet after kidney transplantation, utilisation of non-heart-beating donors, single-donor islet transplantation and living-donor islet transplantation. These advances were based on revised immunosuppression Protocols, improved pancreas procurement and islet isolation methods, and enhanced islet engraftment. Further improvements are necessary to make islet transplantation a routine clinical treatment. To synergise efforts towards a cure for type 1 diabetes, a Diabetes Research Institute (DRI) Federation is currently being established to include leading diabetes research centres worldwide, including DRIs in Miami, Edmonton and Kyoto among others.
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Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center
Transplantation, 2004Co-Authors: John A. Goss, Rodolfo Alejandro, F. Charles Brunicardi, Sarah E. Goodpastor, Merle Barth, George D. Soltes, Alan J. Garber, Dale J. Hamilton, Camillo RicordiAbstract:Background. With the development of the Edmonton Protocol, pancreatic islet transplantation (PIT) now offers insulin-dependent diabetic patients metabolic stability. The PIT Food and Drug Administration (FDA) regulations, pancreatic islet isolation (PII) techniques, and clinical PIT Protocols are challenging and make PIT program development daunting. Purpose. Review of the establishment of a PIT program through a collaborative relationship with a remote PIT/PII center. Methods. Four key elements are required: (1) development of a collaborative relationship with an established PIT/PII center, (2) achievement of institutional review board and FDA approval at both centers, (3) generation of standard operating procedures, and (4) development of a multidisciplinary PIT team. Results. Securing a collaborative relationship with an experienced PIT/PII center permitted our program to develop in less than 18 months. Twenty-two PITs were completed in the first clinical year. Conclusions. Collaboration with an experienced PIT/PII center allows developing programs to focus on patient safety and care, prudent use of pancreata, and consolidates PII expertise and experience.
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Unraveling the Secrets of Single Donor Success in Islet Transplantation
American Journal of Transplantation, 2004Co-Authors: A. M. James Shapiro, Camillo RicordiAbstract:Islet transplantation is emerging as an attractive alternative to solitary pancreas transplantation for a highly select group of patients with severe, labile forms of Type 1 diabetes that had previously tried and failed on intensive insulin therapy. The year 2000 marked a dramatic shift in clinical success with the introduction of the so-called ‘Edmonton Protocol’, which built upon many years of intensive research and extensive collaborations between islet groups worldwide (1,2).
A James M Shapiro - One of the best experts on this subject based on the ideXlab platform.
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human islet mass morphology and survival after cryopreservation using the Edmonton Protocol
Islets, 2013Co-Authors: Priya Miranda, A James M Shapiro, Viswanathan Mohan, Sekhar Ganthimathy, Ranjit Mohan Anjana, S Gunasekaran, Venkatachalam Thiagarajan, Thomas A Churchill, Jonathan R T LakeyAbstract:The aim of this study was to assess recovery, cell death, and cell composition of post-thaw cultured human islets. Cryopreserved islets were provided by the Clinical Islet Transplant Program, Edmonton, Canada. Islets were processed using media prepared in accordance with Pre-Edmonton and Edmonton Protocols. Cryopreserved islets were rapidly thawed and cultured for 24 h, 3 d, 5 d, and 7 d, following which they were processed for histology. Islet quantification, integrity, morphology and tissue turnover were studied via hematoxylin and eosin stained sections. Ultrastructure was studied by electron microscopy and endocrine cell composition by immunohistochemistry. Using the Pre-Edmonton Protocol, islet recovery was 50.1% and islet survival was 50% at 24 h while for the Edmonton Protocol, the islet recovery was 69.4% (p < 0.001) and islet survival, 50% at ≈2.5 d. With an increasing culture duration although the physical integrity was retained there was an increasing loss of cohesivity both at light microscopic and at ultrastructure level regardless of the Protocols used. Percentage islet survival and tissue turnover correlated negatively with culture duration in both Protocols. The Edmonton Protocol appears to preserve the islets better. However, culture duration adversely affects islet survival and quality, indicating the need for more optimal cryopreservation and culture techniques.
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international trial of the Edmonton Protocol for islet transplantation
The New England Journal of Medicine, 2006Co-Authors: A James M Shapiro, Antonio Secchi, Camillo Ricordi, Bernhard J Hering, Hugh Auchincloss, Robert Lindblad, Paul R Robertson, M D Brendel, Thierry Berney, Daniel C BrennanAbstract:Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common Protocol (the Edmonton Protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton Protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)
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current status of pancreatic islet transplantation
Clinical Science, 2006Co-Authors: Shaheed Merani, A James M ShapiroAbstract:DM (diabetes mellitus) is a metabolic disorder of either absolute or relative insulin deficiency. Optimized insulin injections remain the mainstay life-sustaining therapy for patients with T1DM (Type I DM) in 2006; however, a small subset of patients with T1DM (approx. 10%) are exquisitely sensitive to insulin and lack counter-regulatory measures, putting them at higher risk of neuroglycopenia. One alternative strategy to injected insulin therapy is pancreatic islet transplantation. Islet transplantation came of age when Paul E. Lacy successfully reversed chemical diabetes in rodent models in 1972. In a landmark study published in 2000, Shapiro et al. [A. M. Shapiro, J. R. Lakey, E. A. Ryan, G. S. Korbutt, E. Toth, G. L. Warnock, N. M. Kneteman and R. V. Rajotte (2000) N. Engl. J. Med. 343 , 230–238] reported seven consecutive patients treated with islet transplants under the Edmonton Protocol, all of whom maintained insulin independence out to 1 year. Substantial progress has occurred in aspects of pancreas procurement, transportation (using the oxygenated two-layer method) and in islet isolation (with controlled enzymatic perfusion and subsequent digestion in the Ricordi chamber). Clinical Protocols to optimize islet survival and function post-transplantation improved dramatically with the introduction of the Edmonton Protocol, but it is clear that this approach still has potential limitations. Newer pharmacotherapies and interventions designed to promote islet survival, prevent apoptosis, to promote islet growth and to protect islets in the long run from immunological injury are rapidly approaching clinical trials, and it seems likely that clinical outcomes of islet transplantation will continue to improve at the current exponential pace.
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islet graft assessment in the Edmonton Protocol implications for predicting long term clinical outcome
Diabetes, 2004Co-Authors: Cale N Street, Jonathan R T Lakey, A James M Shapiro, Sharleen Imes, Ray V Rajotte, Edmond A Ryan, James Lyon, Jose G Avila, Toshiaki Tsujimura, Gregory S KorbuttAbstract:The success of the Edmonton Protocol for islet transplantation has provided new hope in the treatment of type 1 diabetes. This study reports on the assessment of 83 human islet grafts transplanted using the Edmonton Protocol since 1999. Cellular composition, as assessed by immunohistochemistry, showed a lower islet purity (∼40%) than has been reported in previous studies using dithizone staining to quantitate islet equivalents. Furthermore, grafts were found to contain substantial populations of exocrine and ductal tissue. Total cellular insulin transplanted was 8,097.6 ± 3,164.4 μg/patient, and was significantly lower in bottom gradient layer grafts than top gradient layer or whole/combined grafts ( P
Hirofumi Noguchi - One of the best experts on this subject based on the ideXlab platform.
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Temporal Decline in Sirolimus Elimination Immediately After Pancreatic Islet Transplantation
Drug Metabolism and Pharmacokinetics, 2020Co-Authors: Eriko Sato, Shinichi Matsumoto, Teru Okitsu, Masahiro Shimomura, Ikuko Yano, Hirofumi Noguchi, Yasuhiro Iwanaga, Satohiro Masuda, Toshiya Katsura, Hideo NagataAbstract:Summary: Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton Protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.
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Adhesion characteristics of porcine pancreatic islets and exocrine tissue to coating materials.
Islets, 2018Co-Authors: Yoshiki Nakashima, Naoya Kobayashi, Chika Miyagi-shiohira, Issei Saitoh, Masami Watanabe, Hirofumi NoguchiAbstract:Since the report of the Edmonton Protocol in 2000, islet transplantation has been implemented worldwide, and xenotransplantation using porcine islets has also been reported. In addition, ma...
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Pancreas Procurement and Preservation for Islet Transplantation: Personal Considerations
Journal of Transplantation, 2011Co-Authors: Hirofumi NoguchiAbstract:Pancreatic islet transplantation is a promising option for the treatment of type 1 diabetic patients. After the successful demonstration of the Edmonton Protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas procurement and preservation systems. Since we frequently use pancreata from donors after cardiac death in Japan,we have applied the in situ regional organ cooling system for pancreas procurement to reduce the warm ischemic time. To reduce the apoptosis of pancreatic tissue during cold preservation, we have applied the ductal injection of preservation solution. For pancreas preservation, we use modified Kyoto solution, which is advantageous at trypsin inhibition and less collagenase inhibition. In this paper, we show pancreas procurement and preservation in our group for islet transplantation.
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Improved Method of Human Islet Isolation for Young Donors
Transplantation proceedings, 2010Co-Authors: Masayuki Shimoda, Hirofumi Noguchi, Bashoo Naziruddin, Yasutaka Fujita, Daisuke Chujo, Morihito Takita, H. Peng, Yoshiko Tamura, G.s. Olsen, Koji SugimotoAbstract:Abstract Background Although islet transplantation using young donors is more effective than older donors, islet isolation from young donor is notoriously difficult. This may relate to islet ontogeny and collagen composition in the young pancreas. Therefore, we examined whether a high concentration of collagenase could improve the separation of islets from exocrine tissues resulting in an high islet yield. Methods We used six human pancreata from brain-dead donors of less than 30 years old. Islet isolation was performed based on the Edmonton Protocol with modifications. All pancreata were digested with Collagenase NB1 Premium Grade (Serva). The pancreas was expanded by injecting either 200 mL of cold collagenase solution (2.5 mg/mL, standard group, n = 3) or 100 mL of solution (5 mg/mL, new group, n = 3) in a controlled manner under low pressure for 5 minutes. Then the pressure was raised for another 5 minutes. The following procedure and evaluation were performed based on the Edmonton Protocol. Results Phase II time in the new group was significantly shorter than the standard group. The ratio of embedded islets in the new group was significantly lower than the standard group. The postpurification islet equivalents per pancreas weight (IEQ/g) and the recovery rate in the new group were higher than the standard group, but not significantly. There was no significant difference in the postpurification purity, viability, and final tissue volume. Conclusion Our simple modification with an initially concentrated collagenase preparation using a syringe significantly improved the ratio of embedded islets, resulting in a higher yield from young donors.
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Comparison of Fresh and Cultured Islets From Human and Porcine Pancreata
Transplantation proceedings, 2010Co-Authors: Hirofumi Noguchi, Bashoo Naziruddin, Masayuki Shimoda, Yasutaka Fujita, Daisuke Chujo, Morihito Takita, H. Peng, Koji Sugimoto, Takeshi Itoh, Yoshiko TamuraAbstract:Abstract Introduction For clinical islet transplantation, many centers have recently introduced of human islet cultures prior to transplantation. They provide flexibility to evaluate isolated islets and pretreat patients. However, isolated islets deteriorate rapidly in culture. In the present study, we compared fresh human and porcine islets with cultured islets for c-Jun NH2-terminal kinase (JNK) activity. Materials and methods Islet isolations from human and porcine pancreata were performed using the standard Ricordi technique with a modified Edmonton Protocol. Isolated islets cultured for 24 hours at 37°C with 5% CO2 in culture medium were evaluated for counts and JNK activity. Results After 24 hours of culture, the percentages of surviving islets were 86.9% for human and 47.3% for porcine sources. JNK activity in isolated islets declined to a low baseline level after 24-hour culture. Conclusion Both human and porcine islets deteriorated rapidly in 24-hour cultures, although the in vitro conditions did not induce JNK activation.
