CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti
Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti
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Brief Report Metabolism

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Abstract

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation.

Authors

Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti

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Figure 2

Inflammatory status before and after allogeneic islet transplantation in patients with type 1 diabetes.

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Inflammatory status before and after allogeneic islet transplantation in...
(A) Human islets (1,000 IEQ/ml) from 44 pancreas preparations processed from February 2007 to June 2010 at San Raffaele Scientific Institute (19 male, 25 female; age, 50 ± 14 years; BMI, 26.3 ± 3.8; purity, 50% ± 24%) were cultured before transplantation, and chemokine/cytokine concentrations after 24 hours were measured in the supernatants. Boxes denote interquartile range; lines within boxes denote median; whiskers denote 5% and 95% limits. (B) Circulating cytokine/chemokine concentrations were evaluated 1, 3, 6, 12, 24, 72, 120, and 168 hours after islet infusion in 11 patients with type 1 diabetes receiving islet transplantation alone at San Raffaele Scientific Institute under 2 protocols: ATG plus low-dose steroids plus IL-1 receptor antagonist (IL1Ra) and (as maintenance) immunosuppression with rapamycin plus MMF (n = 8); and ATG and (as maintenance) immunosuppression with FK506 plus MMF (n = 3). Data are expressed as median fold increase versus basal at each time point. Mean basal concentrations are shown below. Statistical analysis was performed by Mann-Whitney U test (black bars, P ≤ 0.05; gray bars, P = NS). nt, not tested.