Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Mar 24, 2016; 6(1): 206-214
Published online Mar 24, 2016. doi: 10.5500/wjt.v6.i1.206
Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation
Adrian D Hibberd, David A Clark, Paul R Trevillian, Patrick Mcelduff
Adrian D Hibberd, David A Clark, Paul R Trevillian, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia
Adrian D Hibberd, David A Clark, Paul R Trevillian, Hunter Transplant Research Foundation, Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
Adrian D Hibberd, Paul R Trevillian, Patrick Mcelduff, School of Medicine and Public Health, University of Newcastle, Callaghan, Newcastle, NSW 2308, Australia
Author contributions: Hibberd AD designed the study; Clark DA carried out the experiments; Mcelduff P analysed the data, justified the statistical tools used and constructed the figures; Hibberd AD, Clark DA, Trevillian PR and Mcelduff P all contributed to the interpretation of the data analyses; Hibberd AD and Mcelduff P drafted the manuscript; Hibberd AD, Clark DA, Trevillian PR and Mcelduff P all provided critical intellectual comment about the manuscript; all authors reviewed and approved the final manuscript.
Supported by Kiriwina Investments Limited of Australia.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Care and Ethics Committee of the University of Newcastle, Australia ( ACEC numbers 338 0693; 442 0894; 385 0697; 853 0805).
Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.
Data sharing statement: Technical appendix and dataset are available from the corresponding author at adrian.hibberd@hnehealth.nsw.gov.au.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Adrian D Hibberd, MD, FRACS, FACS, Professor of Surgery, Newcastle Transplant Unit, Division of Surgery, John Hunter Hospital, Hunter Region Mail Centre, PO Box 1083, Newcastle, NSW 2310, Australia. adrian.hibberd@hnehealth.nsw.gov.au
Telephone: +61-4-12896432 Fax: +61-2-49275900
Received: June 30, 2015
Peer-review started: July 4, 2015
First decision: October 16, 2015
Revised: December 3, 2015
Accepted: December 29, 2015
Article in press: January 4, 2016
Published online: March 24, 2016
Processing time: 262 Days and 18.9 Hours
Abstract

AIM: To investigate the interaction between castanospermine and cyclosporin A (CsA) and to provide an explanation for it.

METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG (donor) and DA (recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity.

RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and CsA in the prolongation of cardiac allograft survival for dose ranges of CsA by castanospermine of (0 to 2) mg/kg by (0 to 200) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and (0 to 3) mg/kg by (0 to 100) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of CsA. On the contrary, cessation of castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA level (P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction.

CONCLUSION: There is synergistic interaction between castanospermine and CsA in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of CsA provides an explanation.

Keywords: Cardiac transplantation; Castanospermine; Cyclosporin A; Positive interaction; Mixed lymphocyte reaction

Core tip: The authors have established that a biological, castanospermine, interacts with cyclosporin A (CsA) in a synergistic manner when prolonging the survival of cardiac allografts in inbred rats. They suggest that the explanation is not its effect on the mixed lymphocyte reaction nor interference in the metabolism of CsA but rather an inhibition of migration through the basement membrane of the vasculature. They suggest that its effect on heparanase in mononuclear cells and heparan sulphate in the allograft should now be studied. This immunosuppressant holds promise of safe dose reduction of CsA but further assessment of its safety remains.