Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets

Abstract

Mizoribine (MZ) inhibits the differentiation and proliferation of helper T and B cells after antigen recognition by suppressing the purine biosynthesis pathway and nucleic acid synthesis. MZ has been used in kidney transplantation, but distinct data are unavailable for islet transplantation. The present study investigated the efficacy of MZ for islet xenotransplantation. Immunosuppressive effects of MZ were determined by mixed lymphocyte reaction (MLR) assay in vitro. Toxicities for Wistar rat islets were determined by adenosine triphosphate (ATP) contents of islets during 3-day culture and stimulation index in response to glucose after culture. Immunosuppressive effects in vivo were tested in a Wistar-to-B6 islet xenotransplantation model. MZ was administered continuously for 28 days subcutaneously or intramuscularly. MZ inhibited MLR response by approximately 50% at 0.1 µg/ml. ATP contents decreased with MZ >100 µg/ml, while stimulation index was maintained. Continuous infusion of MZ at 10 mg/kg maintained blood concentrations at 0.13-0.19 µg/ml, while intramuscular injection of MZ at 100 mg/kg/day (peak 520 µg/ml at 1 h postinjection) resulted in below measurable levels (<0.03 µg/ml) within 24 h. Graft survival was significantly prolonged following continuous infusion of 10 mg/kg/day compared to controls (31.0 ± 9.5 vs. 13.2 ± 5.2 days; p = 0.002). Furthermore, animals with intramuscular injection at doses of 3.2, 10, or 100 mg/kg/day showed significantly longer graft survival (20.0 ± 7.5, 22.0 ± 7.31, and 24.5 ± 8.1 days, respectively; p < 0.05 each). Histological examination showed significant suppression of lymphocyte infiltration by MZ administration. MZ showed immunosuppressive effects in an experimental islet xenotransplantation model without adverse effects on endocrine function of islet grafts.

Calcified nodule formation by dental pulp cells derived from rats after subcutaneous injection of an immunosuppressant

“…It was previously demonstrated to markedly inhibit T cell proliferation and the expression of T cell surface activation molecules [28]. MZR may not damage normal cells or nucleic acids [29]. In primary cultures of rDPCs in T-25 flasks, a long time was needed for cells to become confluent.…”

Xenotransplantation literature update, July–August 2012

“…Mizoribine (MZ) inhibits the differentiation and proliferation of helper T and B cells after antigen recognition and has been used in clinical kidney transplantation. Yamashita et al [3] assessed the applicability of MZ in vitro and in vivo in a rat-tomouse islet xenotransplantation model. In mixed lymphocyte reactions, MZ significantly inhibited the mouse splenocyte response against rat responder cells at ‡0.1 lg/ml.…”

“…Yamashita et al. [3] assessed the applicability of MZ in vitro and in vivo in a rat‐to‐mouse islet xenotransplantation model. In mixed lymphocyte reactions, MZ significantly inhibited the mouse splenocyte response against rat responder cells at ≥0.1 μg/ml.…”