Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets
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 pre...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2012-03-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368911X605457 |
| _version_ | 1818974826945052672 |
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| author | Michitoshi Yamashita Takuro Saito Kazuya Ise Show Ishii Yoshihiro Satoh Takaharu Saito Ikuro Oshibe Hirofumi Shimizu Akira Kenjo Takashi Kimura Mitsukazu Gotoh M.D. |
| author_facet | Michitoshi Yamashita Takuro Saito Kazuya Ise Show Ishii Yoshihiro Satoh Takaharu Saito Ikuro Oshibe Hirofumi Shimizu Akira Kenjo Takashi Kimura Mitsukazu Gotoh M.D. |
| author_sort | Michitoshi Yamashita |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T15:46:14Z |
| format | Article |
| id | doaj.art-377b3d606350442d9a9bc33a90ca2750 |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-12-20T15:46:14Z |
| publishDate | 2012-03-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-377b3d606350442d9a9bc33a90ca27502022-12-21T19:34:56ZengSAGE PublishingCell Transplantation0963-68971555-38922012-03-012110.3727/096368911X605457Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on IsletsMichitoshi Yamashita0Takuro Saito1Kazuya Ise2Show Ishii3Yoshihiro Satoh4Takaharu Saito5Ikuro Oshibe6Hirofumi Shimizu7Akira Kenjo8Takashi Kimura9Mitsukazu Gotoh M.D.10Department of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanDepartment of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, JapanMizoribine (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.https://doi.org/10.3727/096368911X605457 |
| spellingShingle | Michitoshi Yamashita Takuro Saito Kazuya Ise Show Ishii Yoshihiro Satoh Takaharu Saito Ikuro Oshibe Hirofumi Shimizu Akira Kenjo Takashi Kimura Mitsukazu Gotoh M.D. Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets Cell Transplantation |
| title | Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets |
| title_full | Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets |
| title_fullStr | Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets |
| title_full_unstemmed | Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets |
| title_short | Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets |
| title_sort | mizoribine as sole immunosuppressive agent in islet xenotransplantation models a candidate immunosuppressant causing no adverse effects on islets |
| url | https://doi.org/10.3727/096368911X605457 |
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