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
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Clinical Trial, Phase II
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Comparative Study
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Blood Glucose / analysis
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Cell Survival / drug effects
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Chemokine CXCL1 / biosynthesis
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Chemokine CXCL1 / genetics
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Chemokine CXCL1 / physiology*
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Diabetes Mellitus, Experimental / blood
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / surgery
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / surgery*
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Drug Evaluation, Preclinical
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Female
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Graft Rejection / prevention & control
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Graft Survival / drug effects
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Humans
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Interleukin-8 / physiology*
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Islets of Langerhans / immunology
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Islets of Langerhans / metabolism*
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Islets of Langerhans / pathology
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Islets of Langerhans Transplantation / immunology*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Middle Aged
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Natural Killer T-Cells / immunology
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Neutrophils / immunology
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Pilot Projects
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Receptors, Interleukin-8A / antagonists & inhibitors
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Receptors, Interleukin-8A / physiology*
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Receptors, Interleukin-8B / antagonists & inhibitors
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Receptors, Interleukin-8B / deficiency
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Receptors, Interleukin-8B / genetics
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Receptors, Interleukin-8B / physiology*
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Treatment Outcome
Substances
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Blood Glucose
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CXCL1 protein, human
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CXCL8 protein, human
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Chemokine CXCL1
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Cxcl1 protein, mouse
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Interleukin-8
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Receptors, Interleukin-8A
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Receptors, Interleukin-8B
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Sulfonamides
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reparixin