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Clinical Trial
. 2012 Oct;122(10):3647-51.
doi: 10.1172/JCI63089. Epub 2012 Sep 17.

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Antonio Citro  1 , Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti
Affiliations
Clinical Trial

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Antonio Citro et al. J Clin Invest. 2012 Oct.

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.

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Figures

Figure 1
Figure 1. Genetic and pharmacologic blockade of the CXCL1-CXCR1/2 axis.
(A) Kaplan-Meier analysis for achieving normoglycemia (<200 mg/dl) in Cxcr2–/– (n = 7) and Cxcr2+/+ (n = 8) alloxan-induced severely diabetic BALB-c mice transplanted with 350 Cxcr2+/+ syngeneic islets through the portal vein. Also shown is achievement of normoglycemia in alloxan-treated severely diabetic C57BL/6 mice transplanted (Tx) with 150 IEQs (n = 46) or 250 IEQs (n = 17) through the portal vein in the presence of reparixin (n = 25 [150 IEQs]; 9 [250 IEQs]) or vehicle (n = 21 [150 IEQs]; 8 [250 IEQs]). Differences were tested using log-rank statistic. The treatment window is shaded gray. (B) CXCR2 expression on IHLs from untreated control mice measured by flow cytometry 5 days after islet transplantation. (C) C57BL/6 recipients were transplanted with 400 C57BL/6 syngeneic or BALB-c allogeneic IEQs into the portal vein in the presence of either reparixin or vehicle. 6 mice (3 reparixin; 3 vehicle) were analyzed per time point. IHL populations were analyzed by flow cytometry. Data are mean ± SEM. For statistical comparisons, see Supplemental Table 1.
Figure 2
Figure 2. Inflammatory status before and after allogeneic islet transplantation in patients with type 1 diabetes.
(A) Human islets (1,000 IEQ/ml) from 44 pancreas preparations processed from February 2007 to June 2010 at San Raffaele Scientific Institute (19 male, 25 female; age, 50 ± 14 years; BMI, 26.3 ± 3.8; purity, 50% ± 24%) were cultured before transplantation, and chemokine/cytokine concentrations after 24 hours were measured in the supernatants. Boxes denote interquartile range; lines within boxes denote median; whiskers denote 5% and 95% limits. (B) Circulating cytokine/chemokine concentrations were evaluated 1, 3, 6, 12, 24, 72, 120, and 168 hours after islet infusion in 11 patients with type 1 diabetes receiving islet transplantation alone at San Raffaele Scientific Institute under 2 protocols: ATG plus low-dose steroids plus IL-1 receptor antagonist (IL1Ra) and (as maintenance) immunosuppression with rapamycin plus MMF (n = 8); and ATG and (as maintenance) immunosuppression with FK506 plus MMF (n = 3). Data are expressed as median fold increase versus basal at each time point. Mean basal concentrations are shown below. Statistical analysis was performed by Mann-Whitney U test (black bars, P ≤ 0.05; gray bars, P = NS). nt, not tested.
Figure 3
Figure 3. Reparixin treatment influences allogeneic islet transplantation outcome in patients with type I diabetes.
(A) Individual patients during 3 months of follow-up after single islet transplantation for patients receiving reparixin and controls without reparixin treatment. Shown are fasting C-peptide, change in average daily insulin requirement, and HbA1c (expressed as an absolute decrease from pretransplant values). (B) Mixed-meal tolerance test (MMTT) 1 month after islet infusion. MMTT was performed after an overnight fast, as described by Greenbaum (16). Maximum and area under the curve (AUC) of C-peptide is shown. (C) Individual islet estimated function (IEF; ref. 17) after single islet transplantation in the presence or absence of reparixin treatment. All comparisons were made using Mann-Whitney test. *P ≤ 0.05.
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