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OBJECTIVE Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.

Islet transplantation is one of the most promising and effective therapies for restoring normoglycemia in type 1 diabetes (T1D) patients, but islet engraftment is one of the main obstacles hampering long-term success. Monitoring graft loss, caused either by immunological or nonimmunological events, occurring in the first phase after transplantation and at later stages of a patient's life is a very important issue. Among the imaging approaches previously applied, magnetic resonance imaging (MRI) monitoring of islet fate following labeling with superparamagnetic iron oxide agents yielded promising results. The aim of this study was to translate into patients the method of islet labeling and MRI monitoring developed in our preclinical setting and to compare imaging results with graft clinical outcome. Three T1D patients and one nondiabetic patient undergoing autotransplantation following subtotal pancreatectomy received Endorem®-labeled islets. Patients were monitored by MRI and metabolically (HbA1c, exogenous insulin requirement, and C-peptide, TEF) at 1, 3, and 7 days following transplantation and once a month up to 10 months. Labeled transplanted islets appeared as hypointense areas scattered within the liver parenchyma, whose absolute number at 24 h after transplantation reflected the labeling efficiency. In patients #1 and #3 with good midterm graft function, MRI follow-up showed an important early loss of hypointense spots followed by a slow and progressive disappearance at later timepoints. Graft loss of function in patient #2 4 weeks after transplantation was associated with the complete disappearance of all hypointense signals. The autotransplanted patient, stably insulin free, showed no significant signal reduction during the first 3 days, followed by loss of spots similar to a patient with good midterm graft function. These results suggest that MRI monitoring of islet transplantation at early time points could represent a meaningful readout for helping in predicting transplant failure or success, but its relevance for mid/long-term islet function assessment appears evanescent.

In the present study we analysed the changes in cytoskeletal actin in lymphoid cells following IL-2 activation and during cell interactions by means of light and electron microscopy, immunofluorescence and molecular analysis. By morphological analysis we observed a higher fluorescence in the activated cells than in the quiescent ones with no modifications in the cytoskeleton pattern comparing activated to resting cells. The results of molecular analysis indicate that, after IL-2 activation, there is a reorganisation of the actin component of the cell cytoskeleton accompanied by the differential expression of the corresponding genes. A future study will be extended to the analysis of others components of the cytoskeleton network.

The aim of this study was to investigate liver microvascular adaptation following the intraportal infusion of pancreatic islets (pancreatic islet transplantation [islet-tx]) in diabetic patients using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI was performed before and 7 days after islet-tx in six diabetic patients. Initial area under curve (AUC60) and volume transfer coefficient (Ktrans) were assessed as markers of liver perfusion. Clinical and metabolic monthly follow-up was performed in all patients, considering fasting C-peptide and β-score as main indices of graft function. High variability in the response of liver microvasculature to islet infusion was observed: two patients showed a significant reduction in liver perfusion after transplantation (pt.2: AUC60 = −23.4%, Ktrans = −31.7%; pt.4: AUC60 = −23.7%, Ktrans = −27.9%); three patients did not show any significant variation of liver perfusion and one patient showed a significant increase (pt.3: AUC60 = +31%, Ktrans = +42.8%). Interestingly, a correlation between DCE-MRI parameters and indices of graft function was observed and, in particular, both patients with DCE-MRI evidence of posttransplantation liver perfusion reduction experienced premature graft failure. Our preliminary study demonstrated that DCE-MRI may identify different adaptive responses of liver microvasculature in patients submitted to islet-tx. These different responses could have an impact on islet engraftment, although reported findings need confirmation from larger studies.

OBJECTIVE— Islet transplantation alone is an alternative for the replacement of pancreatic endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmonton immunosuppressive protocol (tacrolimus-sirolimus association) on kidney function. RESEARCH DESIGN AND METHODS— Nineteen patients with type 1 diabetes and metabolic instability received islet transplantation alone and immunosuppressive therapy according to the Edmonton protocol. Serum creatinine (sCr), creatinine clearance (CrCl), and 24-h urinary protein excretion (UPE) were assessed at baseline and during a follow-up of 339 patientmonths. RESULTS— After islet transplantation we observed 1) sCr within the normal range in all but two patients in whom sCr increased immediately after islet transplantation, and despite withdrawal of immunosuppression, patients progressed to end-stage renal disease (ESRD); 2) CrCl remained within the normal range for those patients who had normal baseline values and decreased, progressing to ESRD in two patients with a decreased baseline CrCl; and 3) 24-h UPE worsened (300 mg/24 h) in four patients. In the two patients who progressed to ESRD, the worsening of 24-h UPE occurred immediately after islet transplantation. In one patient 24-h UPE worsening occurred at 18 months, and, after withdrawal of immunosuppression, it returned to the normal range. In another patient 24-h UPE increased at 24 months and remained stable while immunosuppression was continued. CONCLUSIONS— In type 1 diabetic patients receiving islet transplantation alone, the association of tacrolimus and sirolimus should be used only in patients with normal kidney function. Alternative options for immunosuppressive treatment should be considered for patients with even a mild decrease of kidney function.

The aim of this study was to characterize two new atypical anti-neuronal antibodies using an immunohistochemical method on rat cerebellum and Western blot techniques with primate cerebellar tissue and with recombinant neuronal proteins. Atypical sera from two patients with paraneoplastic neurological syndromes associated with different tumours were detected. Case number 1 presented cerebellar degeneration and Merkel cell carcinoma and case number 2 paraneoplastic brainstem encephalitis and malignant fibrous histiocytoma. By immunohistochemistry, the two new atypical antibodies showed a similar fibrillar positivity in the molecular and granular layers and around the Purkinje cells. The dot blot with recombinant neuronal proteins (HuD, NOVA-1, CDR62/Yo, Amphiphysin) was negative, whereas the Western blot with neuronal antigens of primate cerebellum identified two different proteins with molecular weights (64 kD in case number 1, and 70 kD in case number 2). In conclusion, the two new antibody reactivities against nerve fibres should be integrated into the diagnostic paraneoplastic neurological syndromes guidelines.

Islet transplantation was proposed more than 10 years ago as treatment for normalising glucose homeostasis in type 1 diabetic patients. Since the beginning it has aroused great interest among diabetic patients being an easy procedure, burdened by minor complications: islet transplantation in fact consists on a transhepatic percutaneous injection under local anaesthesia. The initial clinical outcomes not came up to expectations, being low the insulin independence rate and the long term graft function in recipients. Recently, thanks to the introduction of new immunosuppression strategies, clinical data greatly improved: insulin independence was reached in all recipients and maintained in more than 70% of them 2 years from the transplant. The need of an immunosuppression therapy limits the indication of islet transplantation to diabetic patients already immunosuppressed for a previous organ transplant or to patients with brittle diabetes, that is not controlled also with the new strategies of insulin treatment, with a poor quality of life and an increased rate of diabetic complications. Other problems are represented by the progressive decrease of graft function during long term follow up, and by the low number of organ donors that limits the number of transplantation feasible per year.