CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

J Clin Invest. 2012 Oct;122(10):3647-51. doi: 10.1172/JCI63089. Epub 2012 Sep 17.

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.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Glucose / analysis
  • Cell Survival / drug effects
  • Chemokine CXCL1 / biosynthesis
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / physiology*
  • 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
  • Female
  • Graft Rejection / prevention & control
  • Graft Survival / drug effects
  • Humans
  • Interleukin-8 / physiology*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Islets of Langerhans Transplantation / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Natural Killer T-Cells / immunology
  • Neutrophils / immunology
  • 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*
  • Treatment Outcome

Substances

  • 2-(4-isobutylphenyl)propionylmethanesulfonamide
  • Blood Glucose
  • CXCL1 protein, human
  • CXCL8 protein, human
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Interleukin-8
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Sulfonamides