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.
| Original language | English |
|---|---|
| Pages (from-to) | 3647-3651 |
| Number of pages | 5 |
| Journal | Journal of Clinical Investigation |
| Volume | 122 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 1 2012 |
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ASJC Scopus subject areas
- Medicine(all)
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CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. / 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.
In: Journal of Clinical Investigation, Vol. 122, No. 10, 01.10.2012, p. 3647-3651.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CXCR1/2 inhibition enhances pancreatic islet survival after transplantation
AU - Citro, Antonio
AU - Cantarelli, Elisa
AU - Maffi, Paola
AU - Nano, Rita
AU - Melzi, Raffaella
AU - Mercalli, Alessia
AU - Dugnani, Erica
AU - Sordi, Valeria
AU - Magistretti, Paola
AU - Daffonchio, Luisa
AU - Ruffini, Pier Adelchi
AU - Allegretti, Marcello
AU - Secchi, Antonio
AU - Bonifacio, Ezio
AU - Piemonti, Lorenzo
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867188333&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867188333&partnerID=8YFLogxK
U2 - 10.1172/JCI63089
DO - 10.1172/JCI63089
M3 - Article
C2 - 22996693
AN - SCOPUS:84867188333
VL - 122
SP - 3647
EP - 3651
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -