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. IntroductionAchieving long-lasting insulin independence after portal vein islet transplantation has improved, but remains challenging. Nonspecific immune activation (1-6), along with preexisting and transplant-induced auto-and allospecific immune responses (7-9), are components affecting outcome; these are not fully suppressed by ongoing protocols of generalized immunosuppression. Increasing general immunosuppression potency is not ideal because of side effects. Consequently, the development of novel protocols that specifically target proinflammatory immune cell compartments that impede islet function and survival is compelling.

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

“…Of note, even if batches of control and treatment groups run in parallel at all ages, the rate of T1D onset in 4-week-old NOD mice in the control group was relatively lower than in the 12-week-old mice, and this pattern may have contributed to reducing the impact of the intervention started at the earliest age. Third, we demonstrated that transient CXCR1/2 inhibition is able to reverse diabetes, preserving islet mass after onset (21). This is in agreement with indirect evidence previously reported.…”

“…We recently demonstrated that the inhibition of CXCR1/2 chemokine receptors is crucial for improving both human and murine islet survival after transplantation (21). In this study we hypothesized that CXCR1/2 inhibition may also be functional/effective in preventing inflammatory damage to pancreatic islets during diabetes development.…”

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

“…Collectively, our experiments demonstrate that tumor-produced IL8 chemoattracts and modulates human and mouse MDSC in a fashion that can be interfered with in vivo using the CXCR1/2 blocking agent reparixin, that are under clinical development in oncology (38,39). Given the protumorogenic immunosuppressive function of these myeloid subsets, the IL8-MDSC axis offers an attractive target for cancer immunotherapy strategies.…”

“…Reparixin is a described pharmacological inhibitor of CXCR1 and CXCR2 (39,43). Injection of this compound into mice around the time of IL8 gene transfer almost completely abrogated the attraction of MDSC to the liver (Fig.…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…Pharmacological blockade of CXCR1/2 (the chemokine receptor for CXCL1 and CXCL8) by reparixin has been shown to improve islet transplantation outcome both in a mouse model and in the clinical setting (177).…”