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Background: Pancreatogenic diabetes, a consequence of pancreatic tissue loss following pancreatectomy, poses a significant challenge for patients undergoing pancreatic surgery. Islet autotransplantation (IAT) offers a promising approach to prevent or alleviate pancreatogenic diabetes, but its application has been limited to individuals with painful chronic pancreatitis., Methods: This study presents a 15-y clinical experience with the Milan Protocol, which expands IAT after pancreatectomy to a broader spectrum of patients with malignant and nonmalignant pancreatic diseases. The analysis evaluates feasibility, efficacy, and safety of IAT. Modified Igls criteria validated through the arginine test and mixed meal tolerance tests were used to assess long-term metabolic outcomes., Results: Between November 2008 and June 2023, IAT procedures were performed on 114 of 147 candidates. IAT-related complications occurred in 19 of 114 patients (16.7%), with 5 being potentially serious. Patients exhibited sustained C-peptide secretion over the 10-y follow-up period, demonstrating a prevalence of optimal and good beta-cell function. Individuals who underwent partial pancreatectomy demonstrated superior metabolic outcomes, including sustained C-peptide secretion and a reduced risk of developing diabetes or insulin dependence compared with those who underwent total pancreatectomy. For patients who had total pancreatectomy, the quantity of infused islets and tissue volume were identified as critical factors influencing metabolic outcomes. An increased risk of recurrence or progression of baseline diseases was not observed in subjects with neoplasms., Conclusions: These findings provide valuable insights into the benefits and applications of IAT as a therapeutic option for pancreatogenic diabetes after pancreatic surgery, expanding its potential beyond painful chronic pancreatitis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation., Methods: We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival., Results: We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity., Conclusions: Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.

Background: To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery., Methods: From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy., Results: The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT., Conclusions: Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.

Background: The aim of this study was to characterize the immune response against intrabone marrow (BM-Tx) or intraliver (liver-Tx) transplanted islets in the presence or in the absence of immunosuppression., Methods: Less (C57BL/6 in Balb/c) and highly (Balb/c in C57BL/6) stringent major histocompatibility complex fully mismatched mouse models were used to evaluate the alloimmune response. Single antigen-mismatched mouse model (C57BL/6 RIP-GP in C57BL/6) was used to evaluate the antigen-specific immune response. Mice received tacrolimus (FK-506, 0.1 mg/kg per day)/mycophenolate mofetil (MMF, 60 mg/kg per day), and anti-CD3 (50 μg/day) either alone or in combination., Results: Transplant site did not impact the timing nor the kinetics of the alloimmune and single antigen-specific memory T cell responses in the absence of immunosuppression or in the presence of MMF/FK-506 combination. On the other hand, the median time to graft rejection was 28 ± 5.2 days and 16 ± 2.6 days (P = 0.14) in the presence of anti-CD3 treatment, 50 ± 12.5 days and 10 ± 1.3 days (P = 0.003) in the presence of anti-CD3/MMF/FK-506 treatment for liver-Tx and BM-Tx, respectively. Anti-CD3 did not differentially reach BM and liver tissues but was more effective in reducing graft associated T cell responses in liver-Tx than in BM-Tx., Conclusions: Islets infused in the BM appear less protected from the adaptive immune response in the presence of the anti-CD3 treatment. This result raises some concerns over the potential of the BM as a site for islet allotransplantation.

Background: Our final objective is to develop an adoptive therapy with tolerogenic donor-specific type 1 T regulatory cells for patients with type 1 diabetes undergoing islet transplantation. The achievement of this objective depends on the availability of an immunosuppressive treatment compatible with the survival, function, and expansion of type 1 T regulatory cells., Methods: For this purpose, we designed a single-group, phase 1 to 2 trial with an immunosuppression protocol including: (i) rapamycin treatment before the first islet infusion (starting ≥ 30 days before transplantation); (ii) induction therapy with anti-thymocyte globulin (ATG) instead of anti-interleukin-2Ra monoclonal antibody (after the first islet infusion only); (iii) short-term treatment with steroids and interleukin-1Ra (right before and for 2 weeks after each infusion); rapamycin+mycophenolate mofetil treatment as maintenance therapy. The target enrollment was 10 patients., Results: Ten of 15 patients who started the pretransplant rapamycin treatment completed it. Nine of 10 patients did not complete the induction therapy with ATG, and three of 10 required adaptation of maintenance immunosuppression caused by side effects. Four of 10 patients acquired insulin independence which can be maintained up to year 3 after last infusion. All six other patients have lost their graft, and the early graft loss was associated with lower dose of ATG during induction., Conclusion: This protocol resulted feasible, safe but less efficient in maintaining graft survival during the time than other T-cell depletion-based protocols. An adequate induction at the first infusion should be considered to improve the overall clinical outcome.

Objective: Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects., Methods: To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx., Results: RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection., Conclusion: IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.

Background: The role of recipient hyperglycemia on timing of allograft survival is unknown. In this study, we investigated if and how variation in recipient glycemia affects the ability to achieve and maintain normoglycemia after transplant of C57BL/6 islets into diabetic BALB/c mice., Methods and Results: 85 diabetic BALB/c mice with non-fasting glycaemia ranging between 275 and 600 mg/dL were transplanted with 400 C57BL/6 islets. The time of rejection inversely correlated with the pre-transplant blood glucose concentration (P=0.004). All the 13 mice with normoglycemia beyond 50 days had pretransplant glycemia <450 mg/dL and the presence of autologous beta cell function was demonstrated in 8 (>100 days function) by the persistence of normoglycemia after allograft removal. The presence of immunosuppression (rapamycin plus FK506 plus anti-IL-2Ra chain mAbs, n=31; rapamycin plus IL-10; n=29) removed the influence of pretransplant hyperglycemia but after treatment withdrawn the timing and the probability of graft loss correlate with the pretransplant hyperglycemia. Pretransplant glycemia was inversely correlated with HOMA-B and serum insulin showing that a significant residual beta cell mass was present in mice with glycemia <450 mg/dL., Conclusion: This study demonstrates that the timing of functional loss of islets allotransplantation depends on the degree of recipient hyperglycemia. This potential bias should be kept in count in experimental results and a threshold that excludes moderate diabetes should be used in defining recipient's eligibility.

Human islets have chemotactic activity toward macrophages mediated by the secretion of monocyte chemoattractant protein-1 (CCL2/MCP-1) that negatively affect clinical outcome in islet after kidney recipients. The aim of the present work was to identify the donor features and the variables involved in the procedures of islet isolation associated with islet CCL2/MCP-1 release in vitro. We used a retrospective approach studying the outcome in 170 islet isolations. The univariate analysis demonstrated that CCL2/MCP-1 release was significantly associated with the surgical team in charge for organ harvesting, the proteins for dilution solution, the type of gradient, the type of enzyme, and the donor noradrenalin treatment. The multivariate analysis confirmed that the surgical team (P = 0.001) and the enzyme (P = 0.001) were independently associated with in vitro CCL2/MCP-1 islet release (r(2) = 17%). Strategies aimed to optimize the procedures of organ harvesting and islet isolation may reduce the pro-inflammatory properties of the preparation and therefore may improve islet engraftment.