title: 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.affiliation: San Raffaele Diabetes Research Institute (HSR-DRI), Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Citro
authors.forename: Elisa
authors.initials: E
authors.lastname: Cantarelli
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.forename: Erica
authors.initials: E
authors.lastname: Dugnani
authors.forename: Valeria
authors.initials: V
authors.lastname: Sordi
authors.forename: Paola
authors.initials: P
authors.lastname: Magistretti
authors.forename: Luisa
authors.initials: L
authors.lastname: Daffonchio
authors.forename: Pier Adelchi
authors.initials: PA
authors.lastname: Ruffini
authors.forename: Marcello
authors.initials: M
authors.lastname: Allegretti
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000601:surgery*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010865:Pilot Projects; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin