Pancreas graft salvage after successful endovascular treatment of Y graft pseudoaneurysm.

Pancreas transplantation is the most successful treatment option for patients with autoimmune type 1 diabetes. However, the surgical procedure is associated with high morbidity rates. The present case report describes a patient receiving simultaneous pancreas/kidney transplantation. After initial success, he develops a pseudoaneurysm of the iliac Y graft reconstruction, necessitating elective transplantectomy to avoid rupture. While on the waiting list for this operation, the patient is admitted to another hospital with acute bleeding from the pseudoaneurysm. An endovascular stent is successfully placed into the Y graft, stopping the bleeding with preserved pancreas function. Close follow-up using CT angiography shows successful treatment of the aneurysm. Pancreas graft function remains excellent. Although most experts until now have advised transplantectomy in the case of Y graft aneurysms, this case report advocates stent placement and close monitoring to preserve the pancreatic graft.

Nerve Surgery to Treat Intractable Genitofemoral Neuropathic Pain following Laparoscopic Live Kidney Donation.

To date live laparoscopic donor nephrectomies (LLDN) are frequently performed. The most common complications entail bleeding, wound infection, and incisional hernia. Here we discuss a 50-year-old patient with a severe less known complication, namely, postoperative persistent neuropathic pain in the scrotum and left upper leg. Satisfactory pain control could not be obtained in 3 years of postoperative pain treatment which consisted of neuroleptic drugs, blocks of the L1/L2 dorsal roots with local anaesthetics, and pulsed radiofrequency lesioning. Exploratory laparoscopy was performed to assess the aspect of the genitofemoral nerve (GFN). A hemoclip used for the closure of the ureter at the time of nephrectomy was found in close relation to the GFN. The clip was removed and the GFN was subsequently cut proximal to the side of this clip. Soon after surgery the patient was completely pain-free and could return to his normal activities. Surgery should be considered in case of GFN neuropathic pain following LLDN.

[Transplantation of islets of Langerhans: procedure, indications and challenges]. / Transplantatie van eilandjes van Langerhans.

Pancreatic islet isolation and transplantation are complicated procedures, indicated for a carefully selected group of patients. After isolation from the pancreas, the islets are infused into the portal vein. Allogeneic islet transplantation is performed in patients with diabetes mellitus, who suffer from severe hypoglycaemic events and/or progressive complications. One or more donor pancreases are used, which necessitates immunosuppressive treatment. In autologous islet transplantation, which is performed in patients in whom the pancreas has to be removed due to a non-malignant disease, the patients' own islets are isolated and reinfused. No immunosuppressive treatment is required. Reconstitution of endogenous insulin production in allogeneic islet transplantation leads to marked improvements in glycaemic regulation, protection against severe hypoglycaemic episodes and fewer diabetes-related complications. Autologous islet transplantation allows for preservation of endogenous insulin production, which prevents (unstable) diabetes from occurring. This article describes the indications, procedure and pitfalls of islet isolation and transplantation, including three representative cases.

Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience.

BACKGROUND: Donation after circulatory death (DCD) pancreas transplantation has been shown to be an additional way to deal with donor organ shortages. The results of 5-year DCD pancreas transplantation are presented. METHODS: A retrospective, single-center analysis (2011-2015) was performed to compare the results of donation after brain death (DBD) to DCD pancreas transplantation. RESULTS: During the study period, 104 pancreas transplantations (83 from DBD and 21 from DCD) were performed. Median Pancreas Donor Risk Index (PDRI) was 1.47, (DBD, 1.61 vs DCD, 1.35; P = 0.144). Without the factor DCD, PDRI from DCD donors was significantly lower (DBD, 1.61 vs DCD, 0.97; P < 0.001). Donor age was the only donor-related risk factor associated with pancreas graft survival (Hazard ratio, 1.06; P = 0.037). Postoperative bleeding and kidney delayed graft function occurred more frequently in recipients from DCD (P = 0.006). However, DCD pancreata had a lower incidence of thrombosis. Kidney and pancreas graft survival were equally good in both groups. CONCLUSIONS: Pancreas transplantation from DCD donors yields comparable results to DBD donors when PDRI of DCD is relatively low. Most DCD donors are younger donors with trauma as cause of death. These DCD pancreas grafts may be a better option to cope with increasing organ shortages than exploring the limits with older (and higher PDRI) DBD donors.

Immune responses against islet allografts during tapering of immunosuppression--a pilot study in 5 subjects.

Transplantation of isolated islet of Langerhans cells has great potential as a cure for type 1 diabetes but continuous immune suppressive therapy often causes considerable side effects. Tapering of immunosuppression in successfully transplanted patients would lower patients' health risk. To identify immune biomarkers that may prove informative in monitoring tapering, we studied the effect of tapering on islet auto- and alloimmune reactivity in a pilot study in five transplant recipients in vitro. Cytokine responses to the graft were measured using Luminex technology. Avidity of alloreactive cytotoxic T Lymphocytes (CTL) was determined by CD8 blockade. The influence of immunosuppression was mimicked by in vitro replenishment of tacrolimus and MPA, the active metabolite of mycophenolate mofetil. Tapering of tacrolimus was generally followed by decreased C-peptide production. T-cell autoreactivity increased in four out of five patients during tapering. Overall alloreactive CTL precursor frequencies did not change, but their avidity to donor mismatches increased significantly after tapering (P = 0·035). In vitro addition of tacrolimus but not MPA strongly inhibited CTL alloreactivity during tapering and led to a significant shift to anti-inflammatory graft-specific cytokine production. Tapering of immunosuppression is characterized by diverse immune profiles that appear to relate inversely to plasma C-peptide levels. Highly avid allospecific CTLs that are known to associate with rejection increased during tapering, but could be countered by restoring immune suppression in vitro. Immune monitoring studies may help guiding tapering of immunosuppression after islet cell transplantation, even though we do not have formal prove yet that the observed changes reflect direct effects of immune suppression on immunity.

Relevance of cytotoxic alloreactivity under different immunosuppressive regimens in clinical islet cell transplantation.

Islet or beta cell transplantation provides a promising cure for type 1 diabetes patients, but insulin-independency decreases frequently over time. Immunosuppressive regimens are implemented attempting to cope with both auto- and alloimmunity after transplantation. We analysed the influence of different immunotherapies on autoreactive and alloreactive T cell patterns and transplant outcome. Patients receiving three different immunosuppressive regimens were analysed. All patients received anti-thymocyte globulin induction therapy. Twenty-one patients received tacrolimus-mycophenolate mofetil maintenance immunosuppression, whereas the other patients received tacrolimus-sirolimus (SIR, n = 5) or SIR only (n = 5). Cellular autoreactivity and alloreactivity (CTL precursor frequency) were measured ex vivo. Clinical outcome in the first 6 months after transplantation was correlated with immunological parameters. C-peptide levels were significantly different between the three groups studied (P = 0.01). We confirm that C-peptide production was correlated negatively with pretransplant cellular autoreactivity and low graft size (P = 0.001, P = 0.007 respectively). Combining all three therapies, cellular autoimmunity after transplantation was not associated with delayed insulin-independence or C-peptide production. In combined tacrolimus-SIR and SIR-treated patients, CTL alloreactivity was associated with less insulin independence and C-peptide production (P = 0.03). The percentage of donors to whom high CTLp frequencies were measured was lower in insulin-independent recipients (P = 0.03). In this cohort of islet cell graft recipients, clinical outcome in the first 6 months after transplantation correlates with the applied immunosuppressive regimen. An association exists between insulin-independence and lower incidence of CTL alloreactivity towards donor human leucocyte antigen. This observational study demonstrates the usefulness of monitoring T cell reactivity against islet allografts to correlate immune function with graft survival.

Allograft-specific cytokine profiles associate with clinical outcome after islet cell transplantation.

Islet cell transplantation can cure type 1 diabetes, but allograft rejection and recurrent autoimmunity may contribute to decreasing insulin independence over time. In this study we report the association of allograft-specific proliferative and cytokine profiles with clinical outcome. Peripheral blood mononuclear cells were obtained of 20 islet recipients. Cytokine values in mixed lymphocyte cultures (MLC) were determined using stimulator cells with graft-specific HLA class II. Qualitative and quantitative cytokine profiles were determined before and after islet transplantation, blinded from clinical outcome. Cytotoxic T Lymphocyte precursor (CTLp) assays were performed to determine HLA class I alloreactivity. Allograft-specific cytokine profiles were skewed toward a Th2 or regulatory (Treg) phenotype after transplantation in insulin-independent, but not in insulin-requiring recipients. IFNgamma/IL10 ratio and MLC proliferation decreased after transplantation in insulin-independent recipients (p = 0.006 and p = 0.01, respectively). Production of the Treg cytokine IL10 inversely correlated with proliferation in alloreactive MLC (p = 0.008) and CTLp (p = 0.005). Production of IL10 combined with low-MLC reactivity associated significantly with insulin independence. The significant correlation between allograft-specific cytokine profiles and clinical outcome may reflect the induction of immune regulation in successfully transplanted recipients. Islet donor-specific IL10 production correlates with low alloreactivity and superior islet function.

Transfer of ureteral carcinoma in a transplanted kidney presenting by early stenosis of the proximal ureter.

A 71-yr-old male kidney transplant recipient suffered from delayed graft function. Eighty days after transplantation complete obstruction of the proximal ureter was observed, complicated by recurrent urinary tract infections. Two months later, the donor kidney was removed because of infectious complications and inadequate arterial perfusion. Histological examination of the removed graft showed signs of rejection as well as a low-grade papillary urothelial cell carcinoma of donor origin in the ureter. The remaining donor ureter was removed subsequently and showed no further signs of malignancy. Follow-up of the patient until 12 months after surgery did not reveal recurrence of the tumor. This case report is the first to describe accidental transfer of urothelial cell carcinoma in the ureter by transplantation, highlighting the possibility of malignancy when early stenosis is not related to the anastomosis. It again emphasizes the need for precise and cautious screening of organ donors, especially those of higher age.

Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes.

An immunogenic peptide (p277) from the 60-kDa heat shock protein (hsp60) arrested beta-cell destruction in non-obese diabetic mice. A randomized, double-blind, phase Ib/II clinical trial of DiaPep277 peptide treatment was performed in recent-onset type 1 diabetes patients with remaining insulin production. We studied the immunological efficacy of this peptide therapy and correlated this with clinical outcome. Forty-eight C-peptide-positive patients were assigned subcutaneous injections of 0.2, 1.0 or 2.5 mg p277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). T cell autoimmunity to hsp60, DiaPep277, glutamic acid decarboxylase and tetanus toxoid (recall response control) were assayed by proliferation and cytokine secretion assays (enzyme-linked immunospot) at regular intervals until 18 months after the first injection. All treated patients at each dosage of peptide demonstrated an altered immune response to DiaPep277, while the majority of placebo-treated patients remained non-responsive to treatment (P = 0.00001), indicating a 100% efficacy of immunization. Cytokine production in response to therapy was dominated by interleukin (IL)-10. IL-10 production before therapy and decreasing autoantigen-specific T cell proliferation were associated with beta-cell preservation. Third-party control immune responses were unaffected by therapy. No potentially adverse immunological side effects were noted. DiaPep277 is immunogenic in type 1 diabetic subjects and has immune modulating properties. Immunological monitoring distinguished therapy from placebo treatment and could determine immunological efficacy. Declining or temporary proliferative responses to peptide DiaPep277 treatment may serve as an immunological biomarker for clinical efficacy.

Differential inhibition of autoreactive memory- and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 (sCTLA4), CTLA4Ig and LEA29Y.

Cytotoxic T lymphocyte antigen 4 (CTLA4) is a potent inhibitory co-stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases. An association has been reported of both mRNA expression and serum levels of the soluble splice variant of CTLA4 (sCTLA4) with type 1 diabetes. Furthermore, recombinant fusion proteins CTLA4Ig and LEA29Y have been proposed as therapies for type 1 diabetes. We studied the role of (s)CTLA4 in islet autoimmunity. Binding capacity of the proteins to antigen-presenting cells was determined by flow cytometry in competition and binding assays. Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins CTLA4Ig and LEA29Y was measured in a dose-response lymphocyte stimulation test, using a panel of diabetes-associated T cell clones reactive to islet autoantigens. As controls, mixed lymphocyte reactions (MLR) were performed to assess functionality of these proteins in a primary alloreactive setting. All three CTLA4 molecules were able to bind to antigen-presenting cells and inhibit the expression of CD80/CD86. sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose-dependent manner, whereas CTLA4Ig and LEA29Y were not. Conversely, CTLA4Ig and LEA29Y, rather than sCTLA4, were able to suppress naive alloreactive proliferation in a MLR. Our results indicate a differential role for sCTLA4, CTLA4Ig and LEA29Y proteins in memory versus primary immune responses with implications for efficacy in intervention therapy.