1. CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
- Author
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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, and Piemonti, Lorenzo
- Subjects
Chemokine receptors -- Physiological aspects -- Research ,Type 1 diabetes -- Research -- Patient outcomes -- Drug therapy -- Care and treatment ,Allosteric proteins -- Physiological aspects -- Health aspects -- Research ,Islet cell transplantation -- Health aspects -- Research ,Health care industry - 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., Introduction Achieving long-lasting insulin independence after portal vein islet transplantation has improved, but remains challenging. Nonspecific immune activation (1-6), along with preexisting and transplant-induced auto-and allospecific immune responses (7-9), are [...]
- Published
- 2012
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