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Bernhard J Hering

Publications and source records attributed to Bernhard J Hering.

At least 19 recordsLinked to original sources
PubMed2006

International trial of the Edmonton protocol for islet transplantation.

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 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates.

Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.

Animals↗
PubMed2006

Increasing donor chimerism and inducing tolerance to islet allografts by post-transplant donor lymphocyte infusion.

Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

Adoptive Transfer↗
PubMed2006

Effect of donor age on function of isolated human islets.

This study intended to evaluate the impact of donor age on the function of isolated islets. Analysis of human islets from cadaveric donors (age 16-70 years) was performed using glucose-stimulated insulin release (GSIR) (n = 93), islet ATP content (n = 27), diabetic nude mouse bioassay (n = 72), and the insulin secretory function after single-donor clinical islet allotransplantation (n = 7). The GSIR index was significantly higher in younger donors (age < or =40 years) than in older donors and negatively correlated with the donor age (r = -0.535). Islet ATP was higher in younger donors (115.7 +/- 17.7 vs. 75.7 +/- 6.6 pmol/microg DNA). The diabetes reversal rate of mice with 2,000 IE was significantly higher in younger donors (96 vs. 68%). C-peptide increment to glucose during intravenous glucose tolerance test at days 90-120 after clinical transplantation showed negative correlation with donor age (r = -0.872) and positive correlation with the islet mass (r = 0.832). On the other hand, acute insulin response to arginine only showed correlation with the islet mass and not with donor age. These results show that insulin secretory response to glucose deteriorates with increasing age and that it may be related to changes in ATP generation in beta-cells.

Adenosine Triphosphate↗
PubMed2006

Intrahepatic transplanted islets in humans secrete insulin in a coordinate pulsatile manner directly into the liver.

Intrahepatic islet transplantation is an experimental therapy for type 1 diabetes. In the present studies, we sought to address the following questions: 1) In humans, do intrahepatic transplanted islets reestablish coordinated puslatile insulin secretion? and 2) To what extent is insulin secreted by intrahepatic transplanted islets delivered to the hepatic sinusoids (therefore effectively restoring a portal mode of insulin delivery) versus delivered to the hepatic central vein (therefore effectively providing a systemic form of insulin delivery)? To address the first question, we examined insulin concentration profiles in the overnight fasting state and during a hyperglycemic clamp ( approximately 150 mg/dl) in 10 recipients of islet transplants and 10 control subjects. To address the second question, we measured first-pass hepatic insulin clearance in two recipients of islet autografts after pancreatectomy for pancreatitis versus five control subjects by direct catheterization of the hepatic vein. We report that coordinate pulsatile insulin secretion is reestablished in islet transplant recipients and that glucose-mediated stimulation of insulin secretion is accomplished by amplification of insulin pulse mass. Direct hepatic catheterization studies revealed that intrahepatic islets in humans do deliver insulin directly to the hepatic sinusoid because approximately 80% of the insulin is extracted during first pass. In conclusion, intrahepatic islet transplantation effectively restores the liver to pulsatile insulin delivery.

Adult↗
PubMed2005

Achieving and maintaining insulin independence in human islet transplant recipients.

For islet transplants to complete the transition from clinical research to clinical care restoration of insulin independence must be achieved--as with pancreas transplants--with a single donor. To achieve this critical milestone more consistently it will be imperative to pursue the following complementary strategies simultaneously: 1) enhancing the metabolic potency, inflammatory resilience, and immune stealth of isolated islets; 2) inhibiting the thrombotic and inflammatory responses to transplanted islets; and 3) achieving immune protection with strategies lacking diabetogenic side effects. Maintaining insulin independence will be a different challenge requiring us to clarify whether failure of initially successful islet allografts in type 1 diabetes is related: to 1) failure of immunosuppressive regimens to control alloimmunity and autoimmunity; 2) failure of islet regeneration in the presence of currently applied immunosuppressive regimens; and/or 3) failure of islet neogenesis in the absence of an adequate mass and viability of co-transplanted/engrafted islet precursor cells.

Diabetes Mellitus, Type 1↗
PubMed2005

Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.

In autoimmune type 1 diabetes, pathogenic T lymphocytes are associated with the specific destruction of insulin-producing beta-islet cells. Identification of the autoantigens involved in triggering this process is a central question. Here we examined T cells from pancreatic draining lymph nodes, the site of islet-cell-specific self-antigen presentation. We cloned single T cells in a non-biased manner from pancreatic draining lymph nodes of subjects with type 1 diabetes and from non-diabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from control subjects. The oligoclonally expanded T cells from diabetic subjects with DR4, a susceptibility allele for type 1 diabetes, recognized the insulin A 1-15 epitope restricted by DR4. These results identify insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes.

Alleles↗
PubMed2005

Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes.

CONTEXT: Islet allografts from 2 to 4 donors can reverse type 1 diabetes. However, for islet transplants to become a widespread clinical reality, diabetes reversal must be achieved with a single donor to reduce risks and costs and increase the availability of transplantation. OBJECTIVE: To assess the safety of a single-donor, marginal-dose islet transplant protocol using potent induction immunotherapy and less diabetogenic maintenance immunosuppression in recipients with type 1 diabetes. A secondary objective was to assess the proportion of islet transplant recipients who achieve insulin independence in the first year after single-donor islet transplantation. DESIGN, SETTING, AND PARTICIPANTS: Prospective, 1-year follow-up trial conducted July 2001 to August 2003 at a single US center and enrolling 8 women with type 1 diabetes accompanied by recurrent hypoglycemia unawareness or advanced secondary complications. INTERVENTIONS: Study participants underwent a primary islet allotransplant with 7271 (SD, 1035) islet equivalents/kg prepared from a single cadaver donor pancreas. Induction immunosuppression was with antithymocyte globulin, daclizumab, and etanercept. Maintenance immunosuppression consisted of mycophenolate mofetil, sirolimus, and no or low-dose tacrolimus. MAIN OUTCOME MEASURES: Safety (assessed by monitoring the severity and duration of adverse events) and efficacy (assessed by studying the recipients' insulin requirements, C-peptide levels, oral and intravenous glucose tolerance results, intravenous arginine stimulation responses, glycosylated hemoglobin levels, and hypoglycemic episodes) associated with the study transplant protocol. RESULTS: There were no serious, unexpected, or procedure- or immunosuppression-related adverse events. All 8 recipients achieved insulin independence and freedom from hypoglycemia. Five remained insulin-independent for longer than 1 year. Graft failure in 3 recipients was preceded by subtherapeutic sirolimus exposure in the absence of measurable tacrolimus trough levels. CONCLUSIONS: The tested transplant protocol restored insulin independence and protected against hypoglycemia after single-donor, marginal-dose islet transplantation in 8 of 8 recipients. These results may be related to improved islet engraftment secondary to peritransplant administration of antithymocyte globulin and etanercept. These findings may have implications for the ongoing transition of islet transplantation from clinical investigation to routine clinical care.

Adult↗
PubMed2005

Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates.

Streptozotocin (STZ) is widely applied in animal models of insulin-dependent diabetes mellitus. Adverse effects of STZ mainly concern liver and kidney. In nonhuman primates a single 100-150 mg/kg dose invariably induces diabetes with only rare adverse effects. We report one animal with renal failure necessitating sacrifice. Body weight (age) might be a confounding factor, i.e. older animals might be more vulnerable to STZ-related toxicity. We therefore recommended to administer STZ on a mg/m2 basis and not on a mg/kg basis. In our islet transplantation program nonhuman primates with STZ-induced diabetes received transplants under chronic immunosuppression including calcineurin inhibitors (cyclosporine, tacrolimus), drugs in the rapamycin class affecting growth factor-induced cell proliferation, and the sphingosine 1-phosphate receptor antagonist FTY720. Four animals developed renal failure and had to be sacrificed, most likely caused by cyclosporine. Kidney histology was typical for cyclosporine toxicity including thrombotic microangiopathy in glomeruli and fibrinoid necrosis of arteries, and for STZ toxicity including acute tubular necrosis and accumulations of erythroid precursors. This adverse effect was observed at a pharmacologically active cyclosporine exposure. Additionally, six diabetic animals without major adverse effects during cyclosporine or tacrolimus treatment are presented. We conclude that cyclosporine facilitates renal dysfunction in animals with STZ-induced diabetes, presumably related to an increased vulnerability to a toxic insult after STZ administration.

Animals↗
PubMed2005

Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts.

BACKGROUND: We have previously shown that pig-to-primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non-immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non-human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. METHODS: Liver specimens were collected at sacrifice from seven non-immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real-time reverse transcription polymerase chain reaction (RT-PCR) for species-specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer-efficiencies and normalized to cyclophilin expression. RESULTS: Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post-transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig), significantly increased between early and late time points together with expression of MIP-1alpha, regulated on activation normal T expressed and secreted protein (RANTES) and MCP-1. CCR5 showed only a marginal, non-significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post-transplant. CONCLUSIONS: Our data suggest that CXCR3, with ligands IP-10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non-human primates. Upregulation of RANTES and MIP-1alpha transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP-1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T-cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3-mediated chemoattractant pathway as an immunosuppressive target in pig-to-primate islet xenotransplantation.

Animals↗
PubMed2005

Mycophenolate mofetil in islet cell transplant: variable pharmacokinetics but good correlation between total and unbound concentrations.

The authors investigated the pharmacokinetics of mycophenolic acid over 1 year in 8 Caucasian women undergoing islet cell transplantation. Total mycophenolic acid AUC(0-12) mcg x h/mL before day 60 was 62.1-67.8, declining to 33.6-64.7 thereafter (P = .61). Median total trough concentrations were 1.16-2.90 mcg/mL. Unbound AUC(0-12) was 412-673 ng x h/mL and did not change over time (P = .30). Median percent unbound mycophenolic acid was 0.95% of total concentrations. Individual unbound and total mycophenolic acid concentrations were highly correlated (r2 = 0.94). Total mycophenolic acid trough concentration and total AUC(0-12) were modestly correlated (r2 = 0.65). Intra- and interpatient variability of systemic mycophenolic acid exposure was high. Six patients required dose reductions prior to day 60 due to adverse effects. All subjects achieved insulin independence; 3 later lost graft function. The trend toward higher exposure in the early periods followed by dose reductions suggests that lower initial doses and therapeutic drug monitoring may be necessary.

Adult↗
PubMed2004

Improvement in islet yield from obese donors for human islet transplants.

BACKGROUND: The feasibility of human islet transplantations has been firmly established. To increase the number of islet transplants, the suitability of pancreases from organ donors considered inappropriate for pancreas transplantations must be evaluated. METHODS: We isolated islets from 114 human cadaver donor pancreases by the automated Ricordi method, followed by purification using continuous-density gradients. We divided the pancreases into two groups by donor body mass index (BMI)--group 1: n=51, BMI of 30 or more; group 2: n=63, BMI of less than 30. We compared the results of human islet isolation, in vitro potency assays, and a nude mouse bioassay. RESULTS: In group 1 (vs. group 2), we found a significantly higher mean pancreas weight (109.5+/-30.7 vs. 90.6+/-24.0 g; P=0.0002); higher mean islet equivalents/pancreas, after digestion (442,565+/-238,741 vs. 289,860+/-158,995; P<0.0001) and after purification (319,129+/-164,002 vs. 215,753+/-126,089; P=0.0002); and a higher islet isolation success rate--defined as isolations yielding more than 300,000 islet equivalents/pancreas, with purities of more than 50% (37.3% [19 of 51 pancreases] vs. 15.9% [10 of 63]; P=0.009). Our in vitro potency assays and bioassay uncovered no differences between the two groups. Notably, all except one of the donor BMIs for the successful isolations in group 2 exceeded 26; the mean donor BMI for the successful isolations (27.3+/-3.0, n=10) was significantly higher than for the unsuccessful isolations (24.8+/-3.3, n=53) (P=0.03). CONCLUSIONS: Pancreases from both overweight (BMI > or = 26 but <30) and obese (BMI > or = 30) cadaver donors are suitable for islet isolation and transplantations. Their use could increase the size of the islet donor pool.

Adult↗
PubMed2004

Islet allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720.

OBJECTIVE: In a preclinical, nonhuman primate islet allotransplant model, the authors evaluated a novel immunosuppressive combination of basiliximab for induction and of RAD and FTY720 for maintenance. METHODS: Five ABO-compatible and mixed lymphocyte reactivity-mismatched streptozotocin-induced diabetic juvenile cynomolgus monkeys underwent transplantation intraportally with 48-hr cultured 10,000 islet equivalents per kilogram. Induction immunosuppression was with intravenous basiliximab (10 mg on postoperative days 0 and 4). Maintenance immunosuppression was with RAD (everolimus) (0.075 mg/kg per day administered subcutaneously) and FTY720 (0.3 mg/kg per day administered orally), both administered on day -2 through day 180 posttransplant. RESULTS: All five recipients tolerated their transplants and immunosuppressive therapy well, without adverse events or infectious complications. Insulin requirements pretransplant were 2.6 to 4.0 U/kg per day. All recipients became normoglycemic and insulin-independent posttransplant. Posttransplant serum C-peptide levels averaged 2.7 ng/mL (range, 0.6-6.2 ng/mL). Morning blood glucose levels ranged from less than 100 mg/dL to 150 mg/dL. Posttransplant acute C-peptide response to intravenous arginine averaged 1.3 ng/mL (range, 0.23-2.72 ng/mL). In one recipient with subtherapeutic RAD blood levels on day 7 posttransplant, exogenous insulin was resumed 100 days posttransplant; basal C-peptide levels remained positive in this recipient and averaged 2.6 ng/mL. The other four recipients remained insulin-independent for more than 6 months. CONCLUSIONS: This study provides preliminary evidence of the safety and efficacy of corticosteroid- and calcineurin inhibitor-free immunosuppression in a relevant preclinical transplant model. These findings provide a strong rationale for evaluating this nondiabetogenic regimen in a clinical trial of islet transplants in type 1 diabetic recipients.

Animals↗
PubMed2004

Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis.

BACKGROUND: Total pancreatectomy to treat chronic pancreatitis is associated with severe diabetic control problems in 15% to 75% of patients, causing up to 50% of deaths late postoperatively. We report our experience with islet autotransplants at the time of, or with pancreas allotransplants after, total pancreatectomy. STUDY DESIGN: Between February 1, 1977, and June 30, 2003, we performed 112 islet autotransplants at the time of total pancreatectomy; we also performed 20 pancreas allotransplants in 13 patients who had already undergone total pancreatectomy months to years earlier. RESULTS: Islet autotransplants at the time of total pancreatectomy in patients who had not had previous operations on the body and tail of the pancreas were associated with a high islet yield (>2,500 islet equivalents/kg body weight), and >70% of the recipients achieved complete insulin independence. In contrast, a previous distal pancreatectomy or a Puestow drainage procedure was associated with a low islet yield in 75% of them and with complete insulin independence in <20%. A pancreas allotransplant after total pancreatectomy was not associated with any transplant-related mortality at 1 and 3 years posttransplant. The pancreas graft survival rate at 1 year posttransplant was 77% with tacrolimus-based immunosuppression (versus 67% with cyclosporine). Enteric (over bladder) drainage was preferred to manage exocrine graft secretions, to cure pancreatectomy-induced endocrine and exocrine insufficiency. CONCLUSIONS: Our series shows that pancreas allotransplants can be performed without transplant-related mortality and, when tacrolimus-based immunosuppression is used, with 1-year pancreas graft survival rates >75%. In contrast to a simultaneous islet autotransplant, a pancreas allotransplant has the disadvantage of requiring lifelong immunosuppression, but the advantage of not only curing endocrine but also exocrine insufficiency. Both transplant options, if successful, improve the recipient's quality of life.

Adolescent↗