Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand.

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-2) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2) 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.

• Authors: Ming Yao, Masaaki Watanabe, Sune Sun, Kazuaki Tokodai, Anthony Cerami, Michael Brines, Claes-Göran Östenson, Bo-Göran Ericzon, Torbjörn Lundgren, Makiko Kumagai-Braesch
• Journal: Transplantation (Transplantation) Vol. 104 Issue 10 Pg. 2048-2058 (10 2020) ISSN: 1534-6080 [Electronic] United States
• PMID: 32345869 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Blood Glucose
• Cytokines
• Immunosuppressive Agents
• Inflammation Mediators
• Oligopeptides
• cibinetide
• Tacrolimus

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Cells, Cultured
• Cytokines (metabolism)
• Dendritic Cells (drug effects, immunology, metabolism)
• Diabetes Mellitus, Experimental (blood, immunology, therapy)
• Drug Therapy, Combination
• Graft Survival (drug effects)
• Immunosuppressive Agents (pharmacology)
• Inflammation Mediators (metabolism)
• Islets of Langerhans (drug effects, immunology, metabolism, surgery)
• Islets of Langerhans Transplantation
• Liver (drug effects, metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Oligopeptides (pharmacology)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Tacrolimus (pharmacology)
• Time Factors