Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand
Open Access
- 24 April 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Transplantation
- Vol. 104 (10), 2048-2058
- https://doi.org/10.1097/tp.0000000000003284
Abstract
Background. During intraportal pancreatic islet transplantation (PITx), early inflammatory reactions cause an immediate loss of more than half of the transplanted graft and potentiate subsequent allograft rejection. Previous findings suggest that cibinetide, a selective innate repair receptor agonist, exerts islet protective and antiinflammatory properties and improved transplant efficacy in syngeneic mouse PITx model. In a stepwise approach toward a clinical application, we have here investigated the short- and long-term effects of cibinetide in an allogeneic mouse PITx model. Methods. Streptozotocin-induced diabetic C57BL/6N (H-2b) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2d) mice via the portal vein. Recipients were treated perioperative and thereafter daily during 14 d with cibinetide (120 µg/kg), with or without tacrolimus injection (0.4 mg/kg/d) during days 4–14 after transplantation. Graft function was assessed using nonfasting glucose measurements. Relative gene expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by quantitative polymerase chain reaction. Cibinetide’s effects on dendritic cell maturation were investigated in vitro. Results. Cibinetide ameliorated the local inflammatory responses in the liver and improved glycemic control immediately after allogeneic PITx and significantly delayed the onset of allograft loss. Combination treatment with cibinetide and low-dose tacrolimus significantly improved long-term graft survival following allogeneic PITx. In vitro experiments indicated that cibinetide lowered bone-marrow-derived-immature-dendritic cell maturation and subsequently reduced allogeneic T-cell response. Conclusions. Cibinetide reduced the initial transplantation–related severe inflammation and delayed the subsequent alloreactivity. Cibinetide, in combination with low-dose tacrolimus, could significantly improve long-term graft survival in allogeneic PITx.This publication has 57 references indexed in Scilit:
- Tacrolimus Inhibits the Revascularization of Isolated Pancreatic IsletsPLOS ONE, 2013
- Analysis of Beta-Cell Gene Expression Reveals Inflammatory Signaling and Evidence of Dedifferentiation following Human Islet Isolation and CulturePLOS ONE, 2012
- Advancing islet transplantation: from engraftment to the immune responseDiabetologia, 2011
- Erythropoietin Contrastingly Affects Bacterial Infection and Experimental Colitis by Inhibiting Nuclear Factor-κB-Inducible Immune PathwaysImmunity, 2011
- Erythropoietin protects against diabetes through direct effects on pancreatic β cellsThe Journal of Experimental Medicine, 2010
- Macrophages as novel target cells for erythropoietinHaematologica, 2010
- Symmetric Signaling by an Asymmetric 1 Erythropoietin: 2 Erythropoietin Receptor ComplexMolecular Cell, 2009
- Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietinProceedings of the National Academy of Sciences of the United States of America, 2008
- Erythropoietin: A Potent Inducer of Peripheral Immuno/Inflammatory Modulation in Autoimmune EAEPLOS ONE, 2008
- Discovering erythropoietin's extra-hematopoietic functions: Biology and clinical promiseKidney International, 2006