The Glutathione Depleting Agent Diethylmaleate Prolongs Renal Allograft Survival

• Published in: The Journal of surgical research 1998-06, Vol.77 (1), p.75-79
• Main Authors: Nathens, Avery B., Rotstein, Ori D., Jones, Julia J., Dackiw, Alan P.B., Gorczynski, Reginald
• Format: Article
• Language: English
• Subjects: allograft; Animals; Biological and medical sciences; Cyclosporine - pharmacology; Cytokines - metabolism; diethylmaleate; glutathione; Glutathione - antagonists & inhibitors; Graft Survival - drug effects; ICAM-1; Immunomodulators; Immunosuppressive Agents - pharmacology; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney Transplantation; Male; Maleates - pharmacology; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Pharmacology. Drug treatments; RNA, Messenger - metabolism; Time Factors; tolerance
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1998.5338

Introduction.Intercellular adhesion molecule 1 (ICAM-1) plays an important role in mediating allograft rejection through its role in cellular trafficking and as an important costimulatory signal mediating T cell activation. We have previously reported that systemic administration of the glutathione (GSH) depleting agent diethylmaleate (DEM) prevents upregulation of ICAM-1 in various inflammatory models, suggesting that this agent may offer benefit in preventing allograft rejection. Thus we evaluated the effects of DEM in a murine model of renal transplantation. Methods.Kidneys from C57BL/6 mice were transplanted into MHC incompatible C3H mice. Donors were treated with DEM 1 h prior to sacrifice, whereas recipients received DEM 1 h following transplantation. Animals were followed until the time of death. In separate studies, renal ICAM-1 mRNA expression was evaluated by polymerase chain reaction and the CD4+T cell cytokine profile evaluated in a mixed lymphocyte reaction using C3H responder splenocytes and C57BL/6 stimulator cells. Results.Pretreatment with DEM increased survival from 18.9 ± 3.6 to 30.6 ± 10 days (P< 0.05). This increase in survival was associated with a reduction in renal ICAM-1 mRNA expression. Mixed lymphocyte cultures derived from animals pretreated with DEM demonstrated a reduction in the Th1 cytokines IFN-γ and IL-2 and an increase in the Th2 cytokines IL-4 and IL-10. Conclusion.Administration of DEM with consequent systemic GSH depletion significantly reduces allograft ICAM-1 expression and prolongs graft survival. Although speculative, a shift from a Th1 to a Th2 cytokine response raises the possibility that tolerance induction plays a role in prolonged allograft survival.