Background:Diabetes is a widespread disease with increasing prevalence.Transplantation of islets of Langerhans is a viable treatment for a selected group of patients with repeated hypoglycemic episodes in type 1 diabe...Background:Diabetes is a widespread disease with increasing prevalence.Transplantation of islets of Langerhans is a viable treatment for a selected group of patients with repeated hypoglycemic episodes in type 1 diabetes.The countries where islet transplantation has not been explored suffer from insufficient knowledge concerning key elements of the isolation process.Donor and organ procurement parameters impact human islet yield,although for research purposes,islet yield may be secondary in importance to islet function.This paper will analyze the feasibility of research-only human islet isolation and signify parameters underlying a successful yield in the Indian population.This eventually can make islet transplantation a clinical reality in India.Method:After receiving the consent for procuring brain-dead pancreas from the first-degree of relatives,samples were collected and transported in a transportation buffer at 4℃.The procedure consists of a mechanically enhanced enzymatic digestion of the pancreas,after which it was taken for purification using Ficoll method,followed by islet quality testing.Results:Through 15 isolations done over a span of approximately 2 years during the COVID pandemic in India,we confirm that ischemic time and glycated hemoglobin,each have a negative impact on isolation purity and yield.Notably,extending cold ischemic tim beyond the typical clinical isolation cutoff of 12 hours(to≥18 h)had a huge impact on islet function and yield.Age had a negative correlation with islet yield;however other biological parameters(specifically body mass index)and isolation variables appear to make a significant contribution to the heterogeneity of human islet yield.Our current work demonstrates the feasibility of extending acceptable cold ischemic time for research-focused human islet isolation and highlights the biological variation in isolation of human islets from donors with and without diabetes.Conclusion:India requires establishment of an islet transplant program using the current standard methods of“islet isolation”and donor program and process.Research should focus on improving standards in the islet preparation process to increase the number of successful preparations,shorten the isolation time,and increase patient safety so that the theoretical risk involved can become a practical reality.展开更多
Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes...Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.展开更多
AIM: To evaluate the safety and feasibility of laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with autologous islet transplantation (AIT) for benign tumors of the pancreatic body-neck.
Although allogeneic islet transplantation can successfully cure type 1 diabetes,it has limited applicability.For example,organs are in short supply;several human pancreas donors are often needed to treat one diabetic ...Although allogeneic islet transplantation can successfully cure type 1 diabetes,it has limited applicability.For example,organs are in short supply;several human pancreas donors are often needed to treat one diabetic recipient;the intrahepatic site may not be the most appropriate site for islet implantation;and immunosuppressive regimens,which are associated with side effects,are often required to prolong survival of the islet graft.An alternative source of insulinproducing cells would therefore be of major interest.Pigs represent a possible alternative source of beta cells.Grafting of pig islets may appear difficult because of the immunologic species barrier,but pig islets have been shown to function in primates for at least 6 mo with clinically incompatible immunosuppression.Therefore,a bioartificial pancreas made of encapsulated pig islets may resolve issues associated with islet allotransplantation.Although several groups have shown that encapsulated pig islets are functional in small-animal models,less is known about the use of bioartificial pancreases in large-animal models.In this review,we summarize current knowledge of encapsulated pig islets,to determine obstacles to implantation in humans and possible solutions to overcome these obstacles.展开更多
The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed d...The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords “rodent islet transplantation” to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes.展开更多
BACKGROUND: Islet transplantation is considered a po- tentially curative treatment for diabetic mellitus. The aim of this study was to assess the feasibility of islet transplant through the spleen. METHODS: Both donor...BACKGROUND: Islet transplantation is considered a po- tentially curative treatment for diabetic mellitus. The aim of this study was to assess the feasibility of islet transplant through the spleen. METHODS: Both donor and recipient Wistar rats (BW150± 20 g) were provided by the Animal Center of China Medi- cal University, Shenyang, China. Islets were isolated and purified with the modified Minnesota program. 600-800IE graft islets were handpicked and transplanted through the spleen of diabetic recipients. Blood glucose and insulin were evaluated after operation every other day. IVGTT was performed 10 days after transplantation. RESULTS: 300-400IE islet was procured from one donor rat. Secretion index (SI) of the glucose stress was 5.59± 0.62, showing the graft functioning well. The diabetic rats restored normal blood glucose levels of 3.4-5.4 mmol/L (mean 4.8 mmol/L). Their insulin levels were as normal as 8.5-12.2 μIU/ml. The K value of IVGTT in the rats after transplantation was similar to the normal one. CONCLUSIONS: The islets can be transplanted successfully through the spleen, while avoiding the complications caused by traditional transplantation through the portal vein, such as bleeding and portal vein hypertension. The graft islets loss can be reduced because of less centrifugation and mechanic pressure. In conclusion, transplantation through the spleen is a simple and feasible method.展开更多
Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic isl...Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.展开更多
Up till 2000 when Edmonton group introduced islet transplant procedure in conjunction with a novel glucocorticoid-free immunosuppressive regimen rendering 100% （n=7） of patients with type 1 diabetes insulin-independ...Up till 2000 when Edmonton group introduced islet transplant procedure in conjunction with a novel glucocorticoid-free immunosuppressive regimen rendering 100% （n=7） of patients with type 1 diabetes insulin-independent for at least 1 year, islet transplant was taken into the clinic. Although significant progress in clinical islet transplant has occurred during recent years, challenges remain, including shortage of available donor organs, technical aspects of islet preparation and transplantation, immunological rejection post-transplant, unclear long-term outcomes of islet transplantation. Special attention is given to current limitation in islet transplantation together with new possible strategies that raise expectations for the widespread use of islet transplantation in the future.展开更多
Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,e...Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.展开更多
It has been demonstrated that prolonged graft survival can be achieved through inhibiting the activation of T cells,and addition of soluble CTLA4Ig and OX40Ig proteins to mixed lymphocyte reactions can effectively inh...It has been demonstrated that prolonged graft survival can be achieved through inhibiting the activation of T cells,and addition of soluble CTLA4Ig and OX40Ig proteins to mixed lymphocyte reactions can effectively inhibit T cell proliferation.To explore the potential of this type of treatment in xenotransplantation,we infected streptozotocin-induced diabetic BalB/c mice(H-2d)(200 mg/kg,IV)with 5×108 pfu AdCTLA4Ig-IRES-OX40Ig on day 1 before islets trans-plantation through the tail vein.The results showed that this treatment prolonged the islet xeno-grafts survival significantly.The reaction to exogenous glucose stimulation was normal and the cytokine secretion of the type Th1 cells was inhibited.The AdCTLA4Ig-IRES-OX40Ig-mediated treatment effectively induced the T cells into anergy and the Th1/Th2 cells into deviation.These results strongly supported the therapeutic potential of blockade of costimulation by Ad-CTLA4Ig-IRES-OX40Ig genes transfer in inducing the organ transplantation tolerance.展开更多
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially sev...Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially severe situation,safer and more effective therapeutics are urgently required.Mice have long been the mainstay as preclinical models for basic research on diabetes,although they are not ideally suited for translating basic knowledge into clinical applications.To validate and optimize novel therapeutics for safe application in humans,an appropriate large animal model is needed.Large animals,especially pigs, are well suited for biomedical research and share many similarities with humans,including body size,anatomical features,physiology,and pathophysiology.Moreover,pigs already play an important role in translational studies,including clinical trials for xenotransplantation.Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals,including porcine models of diabetes.This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.展开更多
文摘Background:Diabetes is a widespread disease with increasing prevalence.Transplantation of islets of Langerhans is a viable treatment for a selected group of patients with repeated hypoglycemic episodes in type 1 diabetes.The countries where islet transplantation has not been explored suffer from insufficient knowledge concerning key elements of the isolation process.Donor and organ procurement parameters impact human islet yield,although for research purposes,islet yield may be secondary in importance to islet function.This paper will analyze the feasibility of research-only human islet isolation and signify parameters underlying a successful yield in the Indian population.This eventually can make islet transplantation a clinical reality in India.Method:After receiving the consent for procuring brain-dead pancreas from the first-degree of relatives,samples were collected and transported in a transportation buffer at 4℃.The procedure consists of a mechanically enhanced enzymatic digestion of the pancreas,after which it was taken for purification using Ficoll method,followed by islet quality testing.Results:Through 15 isolations done over a span of approximately 2 years during the COVID pandemic in India,we confirm that ischemic time and glycated hemoglobin,each have a negative impact on isolation purity and yield.Notably,extending cold ischemic tim beyond the typical clinical isolation cutoff of 12 hours(to≥18 h)had a huge impact on islet function and yield.Age had a negative correlation with islet yield;however other biological parameters(specifically body mass index)and isolation variables appear to make a significant contribution to the heterogeneity of human islet yield.Our current work demonstrates the feasibility of extending acceptable cold ischemic time for research-focused human islet isolation and highlights the biological variation in isolation of human islets from donors with and without diabetes.Conclusion:India requires establishment of an islet transplant program using the current standard methods of“islet isolation”and donor program and process.Research should focus on improving standards in the islet preparation process to increase the number of successful preparations,shorten the isolation time,and increase patient safety so that the theoretical risk involved can become a practical reality.
文摘Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.
文摘AIM: To evaluate the safety and feasibility of laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with autologous islet transplantation (AIT) for benign tumors of the pancreatic body-neck.
基金Supported by European Grant Titled Xenome,UE LSHBCT-2006-037377
文摘Although allogeneic islet transplantation can successfully cure type 1 diabetes,it has limited applicability.For example,organs are in short supply;several human pancreas donors are often needed to treat one diabetic recipient;the intrahepatic site may not be the most appropriate site for islet implantation;and immunosuppressive regimens,which are associated with side effects,are often required to prolong survival of the islet graft.An alternative source of insulinproducing cells would therefore be of major interest.Pigs represent a possible alternative source of beta cells.Grafting of pig islets may appear difficult because of the immunologic species barrier,but pig islets have been shown to function in primates for at least 6 mo with clinically incompatible immunosuppression.Therefore,a bioartificial pancreas made of encapsulated pig islets may resolve issues associated with islet allotransplantation.Although several groups have shown that encapsulated pig islets are functional in small-animal models,less is known about the use of bioartificial pancreases in large-animal models.In this review,we summarize current knowledge of encapsulated pig islets,to determine obstacles to implantation in humans and possible solutions to overcome these obstacles.
文摘The purpose of the present study was to organize the parameters involved in experimental allotransplantation in rodents to elaborate the most suitable model to supply the scarcity of islet donors. We used the PubMed database to systematically search for published articles containing the keywords “rodent islet transplantation” to review. We included studies that involved allotransplantation experiments with rodents’ islets, and we reviewed the reference lists from the eligible publications that were retrieved. We excluded articles related to isotransplantation, autotransplantation and xenotransplantation, i.e., transplantation in other species. A total of 25 studies related to allotransplantation were selected for systematic review based on their relevance and updated data. Allotransplantation in rodents is promising and continues to develop. Survival rates of allografts have increased with the discovery of new immunosuppressive drugs and the use of different graft sites. These successes suggest that islet transplantation is a promising method to overcome the scarcity of islet donors and advance the treatment options for type 1 diabetes.
基金The project was supported by a grant from the NationalNatural Scientific Foundation (30371359).
文摘BACKGROUND: Islet transplantation is considered a po- tentially curative treatment for diabetic mellitus. The aim of this study was to assess the feasibility of islet transplant through the spleen. METHODS: Both donor and recipient Wistar rats (BW150± 20 g) were provided by the Animal Center of China Medi- cal University, Shenyang, China. Islets were isolated and purified with the modified Minnesota program. 600-800IE graft islets were handpicked and transplanted through the spleen of diabetic recipients. Blood glucose and insulin were evaluated after operation every other day. IVGTT was performed 10 days after transplantation. RESULTS: 300-400IE islet was procured from one donor rat. Secretion index (SI) of the glucose stress was 5.59± 0.62, showing the graft functioning well. The diabetic rats restored normal blood glucose levels of 3.4-5.4 mmol/L (mean 4.8 mmol/L). Their insulin levels were as normal as 8.5-12.2 μIU/ml. The K value of IVGTT in the rats after transplantation was similar to the normal one. CONCLUSIONS: The islets can be transplanted successfully through the spleen, while avoiding the complications caused by traditional transplantation through the portal vein, such as bleeding and portal vein hypertension. The graft islets loss can be reduced because of less centrifugation and mechanic pressure. In conclusion, transplantation through the spleen is a simple and feasible method.
基金Supported by European Union-NextGenerationEU,through The National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008-C01.
文摘Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.
基金the Major Program of Natural Science Foundation of Fujian Province
文摘Up till 2000 when Edmonton group introduced islet transplant procedure in conjunction with a novel glucocorticoid-free immunosuppressive regimen rendering 100% （n=7） of patients with type 1 diabetes insulin-independent for at least 1 year, islet transplant was taken into the clinic. Although significant progress in clinical islet transplant has occurred during recent years, challenges remain, including shortage of available donor organs, technical aspects of islet preparation and transplantation, immunological rejection post-transplant, unclear long-term outcomes of islet transplantation. Special attention is given to current limitation in islet transplantation together with new possible strategies that raise expectations for the widespread use of islet transplantation in the future.
文摘Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.
基金This work was supported by the National Natural Science Foundation of China(Grant No.39830340).
文摘It has been demonstrated that prolonged graft survival can be achieved through inhibiting the activation of T cells,and addition of soluble CTLA4Ig and OX40Ig proteins to mixed lymphocyte reactions can effectively inhibit T cell proliferation.To explore the potential of this type of treatment in xenotransplantation,we infected streptozotocin-induced diabetic BalB/c mice(H-2d)(200 mg/kg,IV)with 5×108 pfu AdCTLA4Ig-IRES-OX40Ig on day 1 before islets trans-plantation through the tail vein.The results showed that this treatment prolonged the islet xeno-grafts survival significantly.The reaction to exogenous glucose stimulation was normal and the cytokine secretion of the type Th1 cells was inhibited.The AdCTLA4Ig-IRES-OX40Ig-mediated treatment effectively induced the T cells into anergy and the Th1/Th2 cells into deviation.These results strongly supported the therapeutic potential of blockade of costimulation by Ad-CTLA4Ig-IRES-OX40Ig genes transfer in inducing the organ transplantation tolerance.
文摘Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially severe situation,safer and more effective therapeutics are urgently required.Mice have long been the mainstay as preclinical models for basic research on diabetes,although they are not ideally suited for translating basic knowledge into clinical applications.To validate and optimize novel therapeutics for safe application in humans,an appropriate large animal model is needed.Large animals,especially pigs, are well suited for biomedical research and share many similarities with humans,including body size,anatomical features,physiology,and pathophysiology.Moreover,pigs already play an important role in translational studies,including clinical trials for xenotransplantation.Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals,including porcine models of diabetes.This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
