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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3647-3651
Number of pages5
JournalJournal of Clinical Investigation
Volume122
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

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Islets of Langerhans
Transplantation
Ligands
Natural Killer T-Cells
Chemokine Receptors
Type 1 Diabetes Mellitus
Immune System
Neutrophils
Pharmacology
Transplants
Survival
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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

In: Journal of Clinical Investigation, Vol. 122, No. 10, 01.10.2012, p. 3647-3651.

Research output: Contribution to journalArticle

Citro, A, Cantarelli, E, Maffi, P, Nano, R, Melzi, R, Mercalli, A, Dugnani, E, Sordi, V, Magistretti, P, Daffonchio, L, Ruffini, PA, Allegretti, M, Secchi, A, Bonifacio, E & Piemonti, L 2012, 'CXCR1/2 inhibition enhances pancreatic islet survival after transplantation', Journal of Clinical Investigation, vol. 122, no. 10, pp. 3647-3651. https://doi.org/10.1172/JCI63089
Citro, Antonio ; Cantarelli, Elisa ; Maffi, Paola ; Nano, Rita ; Melzi, Raffaella ; Mercalli, Alessia ; Dugnani, Erica ; Sordi, Valeria ; Magistretti, Paola ; Daffonchio, Luisa ; Ruffini, Pier Adelchi ; Allegretti, Marcello ; Secchi, Antonio ; Bonifacio, Ezio ; Piemonti, Lorenzo. / CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 10. pp. 3647-3651.
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