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Pancreas Procurement and Preservation for Islet Transplantation: Personal Considerations  [PDF]
Hirofumi Noguchi
Journal of Transplantation , 2011, DOI: 10.1155/2011/783168
Abstract: 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. 1. Introduction Diabetes mellitus is a devastating disease, and over 200 million people are affected worldwide, thus representing about 6% of the world population. Type 1 diabetes results from the autoimmune-mediated destruction of insulin-secreting β cells in the islets of Langerhans of the pancreas. Pancreatic islet transplantation represents a viable option for the treatment of patients with unstable type 1 diabetes mellitus with frequent severe hypoglycemia and hypoglycemia unawareness [1, 2]. Recent advances in islet transplantation, including the utilization of donors after cardiac death (DCD) [3–6], single-donor islet transplantation [7–10], and living-donor islet transplantation [11], were based on advanced pancreas transport systems [9, 12, 13], improved islet isolation methods [14–17], enhanced islet engraftment [18–21], and revised immunosuppressant protocols [6, 14, 22]. One of the most important issues affecting islet transplantation is concerned with donor quality [23]. Several critical donor factors have been identified, including donor age, body mass index (BMI), cause of death, usage of vasopressor, hypotensive episode, length of hospitalization, blood glucose levels, transaminases level, creatinine levels, cold preservation time, and procurement team [23–26]. Therefore, effective pancreas procurement and preservation are important for successful islet isolation and transplantation. In this paper, the current advances in pancreas procurement and preservation for islet transplantation in our group are described. 2. Pancreas Procurement Pancreata from donors with brain death (DBD) are procured using a standardized technique to minimize warm ischemia. A preservation solution, such as the
Two-layer cold storage method for pancreas and islet cell transplantation  [cached]
Yasuhiro Fujino
World Journal of Gastroenterology , 2010,
Abstract: The two-layer cold storage method (TLM) was first reported in 1988, consisting of a perfluorochemical (PFC) and initially Euro-Collins’ solution, which was later replaced by University of Wisconsin solution (UW). PFC is a biologically inert liquid and acts as an oxygen-supplying agent. A pancreas preserved using the TLM is oxygenated through the PFC and substrates are supplied by the UW solution. This allows the pancreas preserved using the TLM to generate adenosine triphosphate during storage, prolonging the preservation time. In a canine model, the TLM was shown to repair and resuscitate warm ischemically damaged pancreata during preservation, improve pancreas graft survival after transplantation, and also improve the islet yield after isolation. Clinical trials using the TLM in pancreas preservation before whole-pancreas transplantation and islet isolation have shown promising outcomes. We describe the role of the TLM in pancreas and islet transplantation.
Implication of Mitochondrial Cytoprotection in Human Islet Isolation and Transplantation  [PDF]
Yong Wang,Joshua E. Mendoza-Elias,Meirigeng Qi,Tricia A. Harvat,Sang Joon Ahn,Dongyoung Lee,Diana Gutierrez,Hyojin Jeon,Daniel Paushter,José Oberholzer
Biochemistry Research International , 2012, DOI: 10.1155/2012/395974
Abstract: Islet transplantation is a promising therapy for type 1 diabetes mellitus; however, success rates in achieving both short- and long-term insulin independence are not consistent, due in part to inconsistent islet quality and quantity caused by the complex nature and multistep process of islet isolation and transplantation. Since the introduction of the Edmonton Protocol in 2000, more attention has been placed on preserving mitochondrial function as increasing evidences suggest that impaired mitochondrial integrity can adversely affect clinical outcomes. Some recent studies have demonstrated that it is possible to achieve islet cytoprotection by maintaining mitochondrial function and subsequently to improve islet transplantation outcomes. However, the benefits of mitoprotection in many cases are controversial and the underlying mechanisms are unclear. This article summarizes the recent progress associated with mitochondrial cytoprotection in each step of the islet isolation and transplantation process, as well as islet potency and viability assays based on the measurement of mitochondrial integrity. In addition, we briefly discuss immunosuppression side effects on islet graft function and how transplant site selection affects islet engraftment and clinical outcomes. 1. Introduction Since the introduction of the Edmonton Protocol in 2000 [1], human islet transplantation has emerged as a promising therapy for type 1 diabetes mellitus (TIDM) and is the only minimally invasive therapy able to achieve glycemic control without exogenous insulin. As a cell therapy, islet transplantation is a multistep process involving pancreas organ procurement and preservation, tissue digestion and dissociation, islet purification, cell culture, islet transplantation via the hepatic portal vein of the recipient, and maintenance of the graft by nonsteroidal immunosuppressant regiments. Successful islet transplantation is dictated by the cumulative success of the aforementioned steps. To date, islet transplantation has been shown to have variable success in both short- and long-term insulin independence [2–5] and much of this variability is associated with factors from both the organ donor and recipient. In order to maximize the success rate of achieving insulin independence, considerable efforts have been focused on the following aspects: (i) development of a suitable organ preservation solution; (ii) standardization of good manufacturing principles (GMP) in islet isolation; (iii) development of an accurate potency test that can predict islet graft function prior to
Canine Islet Isolation, Cryopreservation, and Transplantation to Nude Mice.  [PDF]
Jui-Chu Huang,Wen-Tsoung Lu,Brend Ray-Sea Hsu,Chien-Hung Kuo
Chang Gung Medical Journal , 2003,
Abstract: Background: Successful human islet transplantation has led to insulin independence intype 1 diabetes. Dogs constitute an animal model for preclinical studies. Wepresent our recent experience in canine islet isolation, cryopreservation andtransplantation.Methods: Twenty-seven pancreases from mongrel dogs, weighing 9-31 kg, wereremoved. Each pancreas was digested with collagenase, and then purified bydensity gradients. Islet number and purity were counted, and the viability ofisolated islets was assessed in vitro by static incubation, perifusion study andin vivo transplantation into nondiabetic or diabetic nude mice. Additionally,freshly isolated islets were cryopreserved for 1 week, and then studied invitro.Results: The islet yield and purity were 121,000
Pancreas Procurement and Preservation for Islet Transplantation: Personal Considerations  [PDF]
Hirofumi Noguchi
Journal of Transplantation , 2011, DOI: 10.1155/2011/783168
Abstract: 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.
Implication of Mitochondrial Cytoprotection in Human Islet Isolation and Transplantation  [PDF]
Yong Wang,Joshua E. Mendoza-Elias,Meirigeng Qi,Tricia A. Harvat,Sang Joon Ahn,Dongyoung Lee,Diana Gutierrez,Hyojin Jeon,Daniel Paushter,José Oberholzer
Biochemistry Research International , 2012, DOI: 10.1155/2012/395974
Abstract: Islet transplantation is a promising therapy for type 1 diabetes mellitus; however, success rates in achieving both short- and long-term insulin independence are not consistent, due in part to inconsistent islet quality and quantity caused by the complex nature and multistep process of islet isolation and transplantation. Since the introduction of the Edmonton Protocol in 2000, more attention has been placed on preserving mitochondrial function as increasing evidences suggest that impaired mitochondrial integrity can adversely affect clinical outcomes. Some recent studies have demonstrated that it is possible to achieve islet cytoprotection by maintaining mitochondrial function and subsequently to improve islet transplantation outcomes. However, the benefits of mitoprotection in many cases are controversial and the underlying mechanisms are unclear. This article summarizes the recent progress associated with mitochondrial cytoprotection in each step of the islet isolation and transplantation process, as well as islet potency and viability assays based on the measurement of mitochondrial integrity. In addition, we briefly discuss immunosuppression side effects on islet graft function and how transplant site selection affects islet engraftment and clinical outcomes.
Regulation of the JNK3 Signaling Pathway during Islet Isolation: JNK3 and c-fos as New Markers of Islet Quality for Transplantation  [PDF]
Saida Abdelli, Klearchos K. Papas, Kate R. Mueller, Mike P. Murtaugh, Bernhard J. Hering, Christophe Bonny
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099796
Abstract: Stress conditions generated throughout pancreatic islet processing initiate the activation of pro-inflammatory pathways and beta-cell destruction. Our goal is to identify relevant and preferably beta-specific markers to assess the activation of beta-cell stress and apoptotic mechanisms, and therefore the general quality of the islet preparation prior to transplantation. Protein expression and activation were analyzed by Western blotting and kinase assays. ATP measurements were performed by a luminescence-based assay. Oxygen consumption rate (OCR) was measured based on standard protocols using fiber optic sensors. Total RNA was used for gene expression analyzes. Our results indicate that pancreas digestion initiates a potent stress response in the islets by activating two stress kinases, c-Jun N-terminal Kinase (JNK) and p38. JNK1 protein levels remained unchanged between different islet preparations and following culture. In contrast, levels of JNK3 increased after islet culture, but varied markedly, with a subset of preparations bearing low JNK3 expression. The observed changes in JNK3 protein content strongly correlated with OCR measurements as determined by the Spearman's rank correlation coefficient rho in the matching islet samples, while inversely correlating with c-fos mRNA expression . In conclusion, pancreas digestion recruits JNK and p38 kinases that are known to participate to beta-cell apoptosis. Concomitantly, the islet isolation alters JNK3 and c-fos expression, both strongly correlating with OCR. Thus, a comparative analysis of JNK3 and c-fos expression before and after culture may provide for novel markers to assess islet quality prior to transplantation. JNK3 has the advantage over all other proposed markers to be islet-specific, and thus to provide for a marker independent of non-beta cell contamination.
Advances and Challenges in Islet Transplantation: Islet Procurement Rates and Lessons Learned from Suboptimal Islet Transplantation  [PDF]
Annette Plesner,C. Bruce Verchere
Journal of Transplantation , 2011, DOI: 10.1155/2011/979527
Abstract: The initial step in successful islet transplantation is procurement of healthy donor islets. Given the limited number of donor pancreata selected for islet isolation and that islets from multiple donors are typically required to obtain insulin independence, it is critical to improve pancreas procurement rates and yield of islets for transplantation. Islets are delicate microorgans that are susceptible to apoptosis, hypoxia, and ischemia during isolation, culture, and the peritransplant period. Once the islets are engrafted, both prompt revascularization and protection from beta-cell death and graft rejection are key to secure long-term survival and function. To facilitate the engraftment of more robust islets suitable for combating the challenging isolation period and proinflammatory transplantation milieu, numerous approaches have been employed to prevent beta-cell dysfunction and death including immune modulation, prevention of apoptosis and hypoxia, as well as stimulation of growth factors, angiogenesis, and reinnervation. In addition to briefly discussing islet isolation procedures, procurement rates, and islet transplantation, the relevant literature pertaining to successful suboptimal islet transplantation is reviewed to provide insight into potential approaches to balance the limited supply of available donor islets.
Advances and Challenges in Islet Transplantation: Islet Procurement Rates and Lessons Learned from Suboptimal Islet Transplantation  [PDF]
Annette Plesner,C. Bruce Verchere
Journal of Transplantation , 2011, DOI: 10.1155/2011/979527
Abstract: The initial step in successful islet transplantation is procurement of healthy donor islets. Given the limited number of donor pancreata selected for islet isolation and that islets from multiple donors are typically required to obtain insulin independence, it is critical to improve pancreas procurement rates and yield of islets for transplantation. Islets are delicate microorgans that are susceptible to apoptosis, hypoxia, and ischemia during isolation, culture, and the peritransplant period. Once the islets are engrafted, both prompt revascularization and protection from beta-cell death and graft rejection are key to secure long-term survival and function. To facilitate the engraftment of more robust islets suitable for combating the challenging isolation period and proinflammatory transplantation milieu, numerous approaches have been employed to prevent beta-cell dysfunction and death including immune modulation, prevention of apoptosis and hypoxia, as well as stimulation of growth factors, angiogenesis, and reinnervation. In addition to briefly discussing islet isolation procedures, procurement rates, and islet transplantation, the relevant literature pertaining to successful suboptimal islet transplantation is reviewed to provide insight into potential approaches to balance the limited supply of available donor islets. 1. Islet Transplantation Islet transplantation is an experimental procedure available to a limited group of type 1 diabetes patients. The procedure was pioneered by Lacy in 1967, when he established a collagenase-based isolation procedure to procure islets from rat pancreata [1]. A few years later, Lacy and colleagues reported the first successful islet transplantation in rodents and primates [2, 3], and by the late 1980s the first islet transplant to obtain insulin independence in a diabetic patient was achieved [4]. Over the next decade, optimization of the islet isolation protocol and use of immunosuppressive drugs with less deleterious side effects became focal points in the field culminating with the establishment of the Edmonton protocol in 2000 [5, 6]. The success of the Edmonton group arose in part because of the use of freshly isolated islets from multiple donors, xenoprotein-free culture conditions, and omitting the use of corticosteroids to prevent rejection. Instead, a combination of immunosuppressive drugs was used that targets IL-2 and hence T- and B-cell stimulation to prevent islet allograft rejection and diminish recurrent autoimmunity. The standard immunosuppressive cocktail used comprises tacrolimus (a calcineurin
Animal Models of Diabetes Mellitus for Islet Transplantation  [PDF]
Naoaki Sakata,Gumpei Yoshimatsu,Haruyuki Tsuchiya,Shinichi Egawa,Michiaki Unno
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/256707
Abstract: Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study. 1. Introduction Islet transplantation is a cell replacement therapy for severe diabetes mellitus (DM), including type 1 DM, that has a long history. In 1967, Lacy and Kostianovsky established a method for isolating islets from rat pancreas using collagenase [1]. Their group also first succeeded in islet intraportal transplantation and reversed diabetes in a rat model [2]. In the clinical setting, the first successful trial of human islet allotransplantation was performed at the University of Pittsburgh in 1990, and five patients achieved an insulin-free condition after islet transplantation [3]. Shapiro and colleagues could significantly improve the outcome of islet transplantation using the “Edmonton Protocol” based on multiple transplantations with a steroid-free immunosuppressive regimen in 2000 [4]. Recent data of clinical islet transplantation revealed that 50% of the patients achieved insulin independence for 5 years [5]. This represents great progress since the rate of being insulin-free was only 10% in the late 1990s [6]. Many studies have been done to improve the success of islet transplantation and will continue to be done in the future. Animal models of DM have contributed much to islet research and to evaluations of isolated human islets for clinical islet transplantation. Good control of blood
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