Effects of Cyclosporine on Transplant Tolerance: The Role of IL-2

Am J Transplant. 2007 Aug;7(8):1907-16. doi: 10.1111/j.1600-6143.2007.01881.x.

Abstract

Allograft(dagger) transplant outcome, rejection or tolerance, depends upon striking a balance between the pertinent cytopathic and regulatory T cells. The drug cyclosporine is a widely used immunosuppressive agent among transplant recipients. Previous studies have demonstrated that cyclosporine blocks apoptosis of activated T cells and the ability of costimulation blockade based regimens to create peripheral transplant tolerance. We now test the hypothesis that the mechanism by which cyclosporine blocks tolerance induction is IL-2 dependent, and linked to a detrimental effect upon T(reg) function. Our study demonstrates that cyclosporine blocks IL-2 gene expression and activation induced cell death (AICD) of alloreactive T effector cells. We also show that cyclosporine abolishes the beneficial effects of a donor specific transfusion (DST) plus anti-CD154 monoclonal antibody (alpha CD154) regimen on enhanced T(regs) function and allograft tolerance induction. Interestingly, provision of IL-2/Fc, a long-lived form of IL-2, completely reverses the detrimental effects of this adjunctive cyclosporine treatment on AICD of alloreactive T effectors, T(regs) function and tolerance induction. Furthermore, in a MHC mismatched islet allograft model, the combination of cyclosporine with IL-2/Fc permitted long-term allograft survival and induced alloantigen specific allograft tolerance. The combination of IL-2/Fc and cyclosporine treatment may provide a new clinical strategy to promote transplant tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CD40 Ligand / pharmacology
  • Carrier Proteins / pharmacology
  • Cell Proliferation / drug effects
  • Cyclosporine / therapeutic use*
  • Cytoskeletal Proteins / pharmacology
  • Disease Models, Animal
  • Dystonin
  • Gene Expression / drug effects*
  • Graft Rejection / genetics
  • Graft Rejection / pathology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • Graft Survival / genetics
  • Immunosuppressive Agents / therapeutic use
  • Interleukin-2 / genetics*
  • Islets of Langerhans Transplantation*
  • Lymphocyte Activation / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Nerve Tissue Proteins / pharmacology
  • Polymerase Chain Reaction
  • Prognosis
  • RNA / genetics*
  • T-Lymphocytes / immunology
  • Transplantation, Homologous

Substances

  • Carrier Proteins
  • Cytoskeletal Proteins
  • Dst protein, mouse
  • Dystonin
  • Immunosuppressive Agents
  • Interleukin-2
  • Nerve Tissue Proteins
  • CD40 Ligand
  • RNA
  • Cyclosporine