Short- and long-term surgical outcomes of total pancreatectomy with islet autotransplantation: A comparative analysis of surgical technique and intraoperative heparin dosing to optimize outcomes.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TP-IAT) is an uncommon surgical procedure with unique perioperative management. We evaluated the short- and long-term morbidity and mortality of TP-IAT to optimize surgical technique and heparin dosing during islet autotransplantation. METHODS: Eighty patients with chronic pancreatitis undergoing TP-IAT were reviewed. Primary outcome was to evaluate morbidity and mortality based on operative technique: classic (resection of antrum) vs pylorus-preserving. Secondary outcome was to evaluate the effect of heparin dosing (<60 vs ≥ 60 units/kg) during islet autotransplantation on postoperative hemorrhage and portal vein thrombosis (PVT) rates. RESULTS: There was no 90-day mortality, and median length of stay was 9 days. All patients underwent an open operation with 53 (66%) pylorus-preserving resections. The 30-day morbidity rate was 39%, with no difference between operative technique (p = 0.82). The median dose was different for each heparin group (<60: 52 units/kg vs ≥ 60: 66 units/kg, p < 0.0001). No difference was observed in postoperative hemorrhage rates between heparin groups (<60: 9% vs ≥ 60: 9%, p = 0.97), with no known incidence of PVT. Median follow-up was 36 months (IQR, 14-71). Morbidity >30 days after TP-IAT was 43% with a higher rate in the pylorus-preserving group (55% vs 15%, p < 0.0001), mainly attributed to marginal ulcer formation (15% vs 0%, p = 0.03). CONCLUSIONS: A classic TP-IAT technique should be universally adopted to achieve optimal outcomes, particularly to prevent the formation of marginal ulcers. When considering PVT versus postoperative hemorrhage risk, a lower heparin dose nearing 50 units/kg is optimal. These findings highlight potential areas for future improvement.

Diabetes-free survival after extended distal pancreatectomy and islet auto transplantation for benign or borderline/malignant lesions of the pancreas.

Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease-free and diabetes-free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow-up was 4 years. We observed no deaths and a low morbidity (nonserious procedure-related complications in 2 of 25 patients). Patient and insulin-independent survival rates at 4 years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes-free survival than did patients without islet autotransplant (P = .04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.

Laparoscopic Total Pancreatectomy With Islet Autotransplantation and Intraoperative Islet Separation as a Treatment for Patients With Chronic Pancreatitis.

Importance: Pain management of patients with chronic pancreatitis (CP) can be challenging. Laparoscopy has been associated with markedly reduced postoperative pain but has not been widely applied to total pancreatectomy with islet autotransplantation (TPIAT). Objective: To examine the feasibility of using laparoscopic TPIAT (L-TPIAT) in the treatment of CP. Design, Setting, and Participants: Thirty-two patients with CP presented for TPIAT at a tertiary hospital from January 1, 2013, through December 31, 2015. Of the 22 patients who underwent L-TPIAT, 2 patients converted to an open procedure because of difficult anatomy and prior surgery. Pain and glycemic outcomes were recorded at follow-up visits every 3 to 6 months postoperatively. Main Outcomes and Measures: Operative outcomes included operative time, islet isolation time, warm ischemia time, islet equivalent (IE) counts, estimated blood loss, fluid resuscitation, and blood transfusions. Postoperative outcomes included length of stay, all-cause 30-day readmission rate, postoperative complications, mortality rate, subjective pain measurements, opioid use, random C-peptide levels, insulin requirements, and glycated hemoglobin level. Results: Of the 32 patients who presented for TPIAT, 20 underwent L-TPIAT (8 men and 12 women; mean [SD] age, 39 [13] years; age range, 21-58 years). Indication for surgery was CP attributable to genetic mutation (n = 9), idiopathic pancreatitis (n = 6), idiopathic pancreatitis with pancreas divisum (n = 3), and alcohol abuse (n = 2). Mean (SD) operative time was 493 (78) minutes, islet isolation time was 185 (37) minutes, and warm ischemia time was 51 (62) minutes. The mean (SD) IE count was 1325 (1093) IE/kg. The mean (SD) length of stay was 11 (5) days, and the all-cause 30-day readmission rate was 35% (7 of 20 patients). None of the patients experienced postoperative surgical site infection, hernia, or small-bowel obstruction, and none died. Eighteen patients (90%) had a decrease or complete resolution of pain, and 12 patients (60%) no longer required opioid therapy at a median follow-up period of 6 months. Postoperative random insulin C-peptide levels were detectable in 19 patients (95%) at a median follow-up of 10.4 months. At a median follow-up of 12.5 months, 5 patients (25%) were insulin independent, whereas 9 patients (45%) required 1 to 10 U/d, 5 patients (25%) required 11 to 20 U/d, and 1 patient (5%) required greater than 20 U/d of basal insulin. The mean (SD) glycated hemoglobin level was 7.4% (0.5%). Conclusions and Relevance: This study represents the first series of L-TPIAT, demonstrating its safety and feasibility. Our approach enables patients to experience shorter operative times and the benefits of laparoscopy, including reduced length of stay and quicker opioid independence.

Immunotoxicological effects of streptozotocin and alloxan: in vitro and in vivo studies.

Streptozotocin (STZ) and alloxan (ALX), widely used to induce diabetes in experimental animals, have different structures and mechanisms of action. We investigated those effects of these drugs on the immune system that might influence engraftment efficiency and graft survival in transplantation models, and their cytotoxicity on hematopoietic cell lines. We used the minimum dose to induce diabetes in a mouse, i.e. 180 mg/kg i.v. STZ and 75 mg/kg i.v. ALX. Both groups exhibited significant decrease in body weight during 4 days post-treatment as compared to controls. We found that blood glucose in ALX-injected mice increased faster than in STZ-injected mice. The total number of recovered splenocytes was lower in STZ-injected animals than in ALX-injected animals. The survival periods of rat islet grafts in recipient mice were longer and more diverse in STZ-injected recipients (7-24 days) compared to ALX-injected recipients (6-7 days). The in vitro study showed that ALX was less cytotoxic in cell lines with IC50 values of 2809, 3679 and >4000 µg/ml for HL60, K562 and C1498 cells respectively. STZ was more toxic, especially in HL60 cells, with IC50 values of 11.7, 904 and 1024 µg/ml for HL60, K562 and C1498 cells respectively. Furthermore, in response to concanavalin A (Con-A), splenocytes from STZ-injected mice produced higher amounts of interferon-gamma (IFN-γ) than those from ALX-injected mice. In conclusion, STZ was more cytotoxic than ALX in vitro and in vivo. STZ caused lymphocytopenia, which may result in longer graft survival in STZ-treated animals than in ALX-treated animals.

Morbidity of total pancreatectomy with islet cell auto-transplantation compared to total pancreatectomy alone.

BACKGROUND: In pancreatitis, total pancreatectomy (TP) is an effective treatment for refractory pain. Islet cell auto-transplantation (IAT) may mitigate resulting endocrinopathy. Short-term morbidity data for TP + IAT and comparisons with TP are limited. METHODS: This study, using 2005-2011 National Surgical Quality Improvement Program data, examined patients with pancreatitis or benign neoplasms. Morbidity after TP alone was compared with that after TP + IAT. RESULTS: In 126 patients (40%) undergoing TP and 191 (60%) patients undergoing TP + IAT, the most common diagnosis was chronic pancreatitis. Benign neoplasms were present in 46 (14%) patients, six of whom underwent TP + IAT. Patients in the TP + IAT group were younger and had fewer comorbidities than those in the TP group. Despite this, major morbidity was more frequent after TP + IAT than after TP [n = 79 (41%) versus n = 36 (29%); P = 0.020]. Transfusions were more common after TP + IAT [n = 39 (20%) versus n = 9 (7%); P = 0.001], as was longer hospitalization (13 days versus 9 days; P < 0.0001). There was no difference in mortality. CONCLUSIONS: This study is the only comparative, multicentre study of TP and TP + IAT. The TP + IAT group experienced higher rates of major morbidity and transfusion, and longer hospitalizations. Better data on the longterm benefits of TP + IAT are needed. In the interim, this study should inform physicians and patients regarding the perioperative risks of TP + IAT.

Relaparotomy for a pancreatic fistula after a pancreaticoduodenectomy: a comparison of different surgical strategies.

INTRODUCTION: A relaparotomy for a pancreatic fistula (PF) after a pancreaticoduodenectomy (PD) is a formidable operation, and the appropriate treatment of anastomotic leakage is under debate. The objective of this study was to compare the outcomes of different strategies in managing the pancreatic remnant during a relaparotomy for PF after a PD. METHODS: In this retrospective study on prospectively collected data, 669 PD were performed between 2004 and 2011. The study group comprised 31 patients requiring a relaparotomy, because of delayed haemorrhage (n = 19) or sepsis (n = 12). The pancreatic stump was treated either using pancreas-preserving techniques (simple drainage or duct occlusion) or completion of a pancreatectomy (CP). In 2008, autologous islet transplantation (AIT) was introduced for endocrine tissue rescue of CP. RESULTS: The mortality rate, blood loss and transfusion requirement were similar for all techniques. Patients undergoing a CP required a further relaparotomy less frequently than patients with pancreas preservation (7% versus 59%, P < 0.01), and the intensive care unit (ICU) stay was reduced after CP (P = 0.058). PF persisted at discharge in 66% of patients after pancreas-preserving techniques. AIT was associated with CP in 7 patients, of whom one died post-operatively. Long-term graft function was maintained in four out of six surviving patients, with one insulin-independent patient at 36 months after transplantation. CONCLUSIONS: When a PF requires a relaparotomy, CP has become our favoured technique. AIT can reduce the metabolic impact of the procedure.

Pancreatic islet transplantation in type 1 diabetes mellitus: an update on recent developments.

Type 1 diabetes mellitus is an autoimmune disease that is characterized by the destruction of the islets of Langerhans cells which produce insulin. The current gold standard treatment is exogenous insulin injection, but this is onerous for the patients, and can lead to severe complications. Another approach involves transplanting pancreatic islet cells in order to restore endogenous insulin production under physiologic regulation. Although there has been some success with this treatment plan, there have been several hurdles. The largest hurdle is improving the 5 year survival of the graft, which is currently at 10%. In order to do so, there has been research into better locations for the graft, better isolation techniques, alternate immune suppression regimens, and novel transplantation methodologies utilizing encapsulated grafts. Another hurdle for pancreatic islet transplantation is that current methodologies require islets from several pancreata in order to create one successful graft, which leads to difficulties since there is a limited supply. However, there has been research looking into single donor transplants and porcine xenografts to increase the supply and address this problem. In this article, we review the current state of research regarding pancreatic islet transplantation.

Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome.

Oxidative stress produced during pancreatic islet isolation leads to significant ß-cell damage. Homeostatic cytokines secreted subsequently to islet transplantation damage ß-cells by generating oxygen free radicals. In this study, exendin-4, a glucagon-like peptide-1 analog improved islet transplantation outcome by increasing the survival of diabetic recipient mice from 58% to 100%. We hypothesized that this beneficial effect was due to the ability of exendin-4 to reduce oxidative stress. Further experiments showed that it significantly reduced the apoptotic rate of cultured ß-cells subjected to hypoxia or to IL-1ß. Reduction of apoptotic events was confirmed in pancreatic islet grafts of exendin-4-treated mice. Exendin-4 enhanced Akt phosphorylation of ß-cells and insulin released from them. It even augmented insulin secretion from islets cultivated at hypoxic conditions. Exposure to hypoxia led to a decrease in the activation of Akt, which was reversed when ß-cells were pretreated with exendin-4. Moreover, exendin-4 increased the activity of redox enzymes in a hypoxia-treated ß-cell line and reduced reactive oxygen species production in isolated pancreatic islets. Recovery from diabetes in mice transplanted with hypoxic islets was more efficient when they received exendin-4. In conclusion, exendin-4 rescued islets from oxidative stress caused by hypoxia or due to cytokine exposure. It improved the outcome of syngenic and xenogenic islet transplantation.

Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation.

BACKGROUND: The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in ß-cells during development but rapidly decreases in postnatal life. METHODS: We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1ß- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. RESULTS: Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (P<0.05, log-rank [Mantel-Cox] test). CONCLUSIONS: Antiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.

Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis.

OBJECTIVES: Chronic pancreatitis (CP) results in an extremely poor quality of life and substantially increases health care utilization. Few data exist regarding the cost-effectiveness of surgical treatment for CP. METHODS: This article examined the cost-effectiveness of total pancreatectomy (TP) with islet cell autotransplantation (IAT) for CP. RESULTS: Sixty patients undergoing TP + IAT and 37 patients undergoing TP were identified. Surgery resulted in significant reduction in opiate use, frequency of hospital admissions, and length of stay as well as visual analog scale scores for pain. Total pancreatectomy + IAT resulted in longer survival than TP alone (16.6 vs 12.9 years); 21.6% of patients with TP + IAT were insulin-independent, and those requiring insulin have reduced daily requirements compared with those having TP alone (22 vs 35 IU). The cost of TP + IAT with attendant admission and analgesia costs over the 16-year survival period was £110,445 compared with £101,608 estimated 16-year costs if no TP + IAT was undertaken. CONCLUSIONS: Total pancreatectomy + IAT is effective in improving pain and reducing analgesia. Islet cell transplantation offers the chance of insulin independence and results in lower insulin requirements, as well as conferring a survival advantage when compared with TP alone. Total pancreatectomy + IAT is cost-neutral when compared with nonsurgical or segmental surgical therapy.

Insulin replacement therapy in patients with type 1 diabetes by isolated pancreatic islet transplantation.

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia which causes micro- and macrovascular complications. A significant increase in diabetes morbidity rate has been observed. It is estimated that in year 2030 there will be 552 million diabetics worldwide. Type 1 diabetes requires lifelong treatment with insulin. The only available treatment of diabetes restoring physiological glucose metabolism is transplantation of pancreatic beta cells in form of pancreas or isolated pancreatic islets transplantation. The treatment restores normoglycemia and reduces chances of complications of diabetes. Over the past 10 years there has been significant progress in the development of the islet transplantation procedure. Constant improvement of the method, in particular the development of islets isolation and sourcing techniques, shows promise. According to the Collaborative Islet Transplant Registry in 1999-2009, there have been performed 1,072 allotransplantations. This paper summarizes the indications and contraindications for the procedure, the transplantation process, as well as the surgical procedure and immunosuppressive treatment. The review presents problems related to pancreatic islet cells transplantation and standard scheme of immunosuppressive treatment, requiring a solution.

An isolated venous sac as a novel site for cell therapy in diabetes mellitus.

BACKGROUND: Transplanting pancreatic islets is of significant interest for type 1 diabetes mellitus. After intraportal injection of islets, inferior engraftment and eventual loss of transplanted islets constitute major limitations. Therefore, alternative approaches will be helpful. Here, we evaluated in animals whether an isolated venous sac would support survival of transplanted islets, along with correction of hyperglycemia. METHODS: Pancreatic islets isolated from adult Lewis rats were transplanted either into an isolated venous sac made from lumbar vein or into the portal vein of syngeneic rats. The integrity and vascular organization of the venous sac was determined by studies of the local microcirculation. The engraftment, survival, and function of transplanted islets were analyzed by histology, including endocrine function in situ and by glycemic control in rats with streptozotocin-induced diabetes. RESULTS: Transplanted islets showed normal morphology with insulin expression in isolated venous sac during the long term. Transplanted islets received blood supply from vasa vasorum and had access to drainage through venous tributaries in the venous sac. This resulted in restoration of euglycemia in diabetic rats. Removal of islet graft-bearing venous sac in diabetic rats led to recurrence of hyperglycemia. By contrast, euglycemia was not restored in rats treated by intraportal transplantation of islets. CONCLUSIONS: We demonstrated that pancreatic islets successfully engrafted and functioned in the isolated venous sac with ability to restore euglycemia in diabetic rats. Therefore, the isolated venous sac offers a new site for transplantation of pancreatic islets. This would be clinically beneficial as an alternative to intrahepatic islet transplantation.

Further evidence for amyloid deposition in clinical pancreatic islet grafts.

BACKGROUND: The reasons for the long-term complete or partial loss of islet graft function are unknown, but there are obviously other reasons than just pure allogeneic graft rejection. Earlier studies have shown that deposition of islet amyloid polypeptide amyloid in transplanted islets may indicate a mechanism for loss of ß cells. MATERIALS AND METHODS: Sections from liver material from four deceased islet-bearing recipients have been scrutinized for the presence of amyloid. Clinical data and certain aspects of the islet graft pathology of these patients have been published previously. RESULT: With this extended histological analysis, we demonstrate the occurrence of amyloid deposits in islets transplanted into the liver in three of four patients with type 1 diabetes. CONCLUSION: The finding adds evidence to the assumption that aggregation of islet amyloid polypeptide might be an important cause of progressing ß-cell dysfunction in clinically transplanted islets.

Clinical islet transplantation: recent advances in the field.

Islet transplantation has emerged as a novel and promising surgical strategy for the treatment of type 1 diabetes mellitus. Almost a decade after the introduction of steroid-free immunosuppression, we have observed steady improvement in the success rate of islet transplantation for the treatment of patients with hypoglycemic unawareness and glycemic lability. However, cell-based therapies face several barriers for widespread success. These barriers include: limited donor pool, innate immune driven inflammation after infusion, acute and chronic immune rejection, and a lack of reliable markers for metabolic follow-up. Recent analysis of data from large multicenter databases suggests that refinements in technical aspects of islet isolation, culture, and immunosuppressive management of the recipient have caused a major and marked improvement observed in recent years in insulin independence rates and metabolic control of the disease. In this review, we highlight the most recent findings published in the literature and focus on important advances in immunosuppression, in vitro beta cell expansion, islet graft assessment, and islet encapsulation, and discuss potential future directions in the field of clinical islet transplantation.

Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes.

OBJECTIVE: Islet autotransplantation (IAT) may decrease the morbidity and mortality of postpancreatectomy diabetes mellitus. The current systematic review and meta-analysis examined the rate of insulin independence (II) and mortality after IAT post-total (TP) or partial pancreatectomy (PP). METHODS: Ovid MEDLINE, EMBASE, Web of Science, SCOPUS and reference lists were searched until 31 January 2011. Eligible studies enrolled adult patients with IAT post-TP or PP, regardless of study design, sample size and language. Two investigators identified eligible studies and extracted data independently. From each study, 95% confidence intervals (CIs) were estimated and pooled using random effects meta-analysis. RESULTS: Fifteen observational studies were eligible (11 IAT post-TP, two post-PP and two including both). The II rates for IAT post-TP at last follow-up and transiently during the study were 4·62 per 100 person-years (95% CI: 1·53-7·72) and 8·34 per 100 person-years (95% CI: 3·32-13·37), respectively. In the later group, patients achieved transient II lasting 15·57 months (95% CI: 10·35-20·79). The II rate at last follow-up for IAT post-PP was 24·28 per 100 person-years (95% CI: 0·00-48·96). Whereas the 30-day mortality for IAT post-TP and post-PP was 5% (95% CI: 2-10%) and 0, respectively, the long-term mortality was 1·38 per 100 person-years (95% CI: 0·66-2·11) and 0·70 per 100 person-years (95% CI: 0·00-1·80) respectively. CONCLUSIONS: IAT postpancreatectomy offers some patients a chance for insulin independence. Better data reporting are essential to establish the risks and benefits of IAT after pancreatic surgery.

Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models.

Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.

Pancreata from pediatric donors restore insulin independence in adult insulin-dependent diabetes mellitus recipients.

CONTEXT: The use of pediatric donors can increase the number of donors available for pancreas transplantation. AIM: The aim of this study was to verify if pancreas transplantation from pediatric donors is as effective as transplantation from adult donors to restore metabolic control in type 1 diabetic patients. MATERIALS AND METHODS: From 2000 to April 2009 we performed 17 pancreas transplantations from pediatric donors: 9 simultaneous kidney-pancreas (SPK), 6 pancreas transplantation alone (PTA), and 2 pancreas after kidney (PAK). All subjects received whole organs with enteric diversion of exocrine secretions; 11 underwent systemic and 6 underwent portal venous graft drainage. The immunosuppressive therapy was as follows: prednisone, mycophenolate mofetil, anti-thymocyte globulin (ATG), and cyclosporine or tacrolimus. The pediatric donor population had a mean age of 15.3 years (range, 12-17), a mean weight of 60.1 kg (range, 42-75), and a mean body mass index (BMI) of 21 (range, 17.9-23.4). RESULTS: After 9 years the overall patient survival rate was 94.12%, whereas the graft survival rate was 63.35%. Normal glucose and insulin levels were maintained either fasting or during oral glucose tolerance test (OGTT). The group of recipients of pediatric organs was compared with patients receiving organs from adult donors (n = 125); the mean glucose values were lower in the pediatric group, whereas insulin production was higher in the adult patients. Early venous thrombosis was 17.6% in the pediatric group and 20% in adult recipients (Fisher exact test, P = not significant [NS]). CONCLUSION: Pediatric donors restored insulin independence in adult diabetic recipients, representing a valid source of organs for pancreas transplantation.

Histologic studies of islets of Langerhans in transplanted pancreata from marginal donors in Japan.

The serious shortage of brain-dead donors leads to the use of pancreata from marginal donors, including cardiac death in Japan. We studied the islet histology of pancreas graft biopsies to investigate the adequacy of using pancreata from marginal donors. Pancreas allograft biopsy was performed originally to diagnose acute rejection (Drachenberg grade I-III) at a mean of 6 months after transplantation. The percentage of beta cells showing oxidative DNA changes, replication, and apoptosis was investigated in 7 recipients of simultaneous pancreas-kidney transplantations with good graft function from marginal donors. Their causes of death were cerebrovascular with donor ages >44 years (n = 3), cardiac (n = 2), and cerebrovascular (n = 2). The percentage of beta cells per islet in the transplanted pancreas (71.9 +/- 3.3%) did not correlate with glycemic control or insulin secretion, but did correlated inversely with donor age (r = -0.81; P < .05). Oxidative DNA changes as revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present in islet cells as well as in the exocrine cells of the transplanted pancreas. The percentage of 8-OHdG-positive cells per pancreas (71.8 +/- 4.5%) did not correlate with glycemic levels, insulin secretion, donor age, or ischemic time. There were no Ki67-positive replicating cells or terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive apoptotic islet cells. Transplanted pancreata from marginal donors showed preserved beta cells and function despite diffuse oxidative changes.

Application of anti-CD103 immunotoxin for saving islet allograft in context of transplantation.

BACKGROUND: Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103(+) cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin (M290-SAP). We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells. METHODS: Flow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo. Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed. RESULTS: M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice (mean survival time, > 100 days vs. < 20 days). C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time 12 - 13 days vs. < 7 days). Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation. CONCLUSION: Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.