KRP-203 Is a Desirable Immunomodulator for Islet Allotransplantation

Abstract

Background. The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogenic and anti-vascularization effects on islet grafts. KRP-203, a sphingosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation. Methods. KRP-203 was administered for 14 d to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multiphoton laser scanning microscope. After islet allotransplantation with either KRP-203 alone, sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunologic characteristics of KRP-203 and sirolimus. Results. No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The multiphoton laser scanning microscope showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%). Conclusions. KRP-203 is a desirable immunomodulator for islet transplantation because of the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.

A gelatin hydrogel nonwoven fabric improves outcomes of subcutaneous islet transplantation

“…An IPGTT was performed 43–47 days after islet transplantation, as described previously 56 . In brief, recipients that had been fasted for 14 h were intraperitoneally infused with D-glucose (1.0 g/kg), and the blood glucose concentrations were determined before and at 5, 10, 15, 20, 25, 30, 45, 60, 90, and 120 min after the injection of glucose.…”

Human A2-CAR T Cells Reject HLA-A2+ Human Islets Transplanted Into Mice Without Inducing Graft-Versus-Host Disease

“…Injection of 3 million A2-CAR T cells into graft-bearing mice caused rapid, synchronous, and antigen-specific rejection of cells transplanted in 2 different sites. This model can be leveraged to test a variety of therapeutic modalities for diabetes, including immunomodulatory drugs, 35,36 devices designed to be immunoprotective, 37 or strategies to cloak SC-β from immune detection. 7,38,39 Limitations of the model are that it does not include an autoimmune component, and the lack of antigen-presenting cells means it would not be suitable for testing some agents, such as those modulating costimulatory molecules.…”

A Gelatin Hydrogel Nonwoven Fabric Combined With Adipose Tissue–Derived Stem Cells Enhances Subcutaneous Islet Engraftment

“…An intraperitoneal glucose tolerance test (IPGTT) was performed 60 to 65 days after islet transplantation, as described previously 26 . The blood glucose curves were generated, and the area under the curve (AUC) was compared.…”