CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

• Published in: The Journal of clinical investigation Vol. 122; no. 10; pp. 3647 - 3651
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2012
• Subjects: 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; Italy; Germany
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci63089

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.