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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Animals, Cyclosporine, Cytokines, Glutathione, Graft Survival, Immunosuppressive Agents, Intercellular Adhesion Molecule-1, Kidney, Kidney Transplantation, Male, Maleates, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, RNA, Messenger, Time Factors.
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Does the glutathione depleting agent diethylmaleate prolong renal allograft survival? Context: 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. 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. 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-gamma and IL-2 and an increase in the Th2 cytokines IL-4 and IL-10.
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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. Final Decision: yes