Journal Article

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

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

2012

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Allosteric proteins / Animals / Biomedical research / Blood Glucose - analysis / Brief Report / Care and treatment / Cell Survival - drug effects / Chemokine CXCL1 - biosynthesis / Chemokine CXCL1 - genetics / Chemokine CXCL1 - physiology / Chemokine receptors / Chemokines / Cytokines / Diabetes / Diabetes Mellitus, Experimental - blood / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - surgery / Diabetes Mellitus, Type 1 - immunology / Diabetes Mellitus, Type 1 - surgery / Drug Evaluation, Preclinical / Drug therapy / Female / Flow cytometry / Graft Rejection - prevention & control / Graft Survival - drug effects / Granulocytes / Health aspects / Humans / Interleukin-8 - physiology / Islet cell transplantation / Islets of Langerhans - immunology / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Islets of Langerhans Transplantation - immunology / Leukocytes / Ligands / Male / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Middle Aged / Natural Killer T-Cells - immunology / Neutrophils - immunology / Patient outcomes / Physiological aspects / Pilot Projects / Receptors, Interleukin-8A - antagonists & inhibitors / Receptors, Interleukin-8A - physiology / Receptors, Interleukin-8B - antagonists & inhibitors / Receptors, Interleukin-8B - deficiency / Receptors, Interleukin-8B - genetics / Receptors, Interleukin-8B - physiology / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Transplants & implants / Treatment Outcome / Type 1 diabetes