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

• Published in: American journal of transplantation Vol. 7; no. 8; pp. 1907 - 1916
• Main Authors: Kang, H. G., Zhang, D., Degauque, N., Mariat, C., Alexopoulos, S., Zheng, X. X.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2007; Blackwell
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Carrier Proteins - pharmacology; CD40 Ligand - 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; IL‐2; Immunosuppressive Agents - therapeutic use; immunosuppressive drugs; Interleukin-2 - genetics; Islets of Langerhans Transplantation; Lymphocyte Activation - genetics; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Nerve Tissue Proteins - pharmacology; Polymerase Chain Reaction; Prognosis; regulatory T cells; RNA - genetics; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes - immunology; tolerance; transplantation; Transplantation, Homologous; Immune response; Cytokine; Transplantation; IL-2; immunosuppressive drugs; Homotransplantation; regulatory T cells; Treatment; Interleukin 2; Surgery; Immune tolerance; T-Lymphocyte; Graft; Ciclosporin; Immunosuppressive agent; Regulatory cell; tolerance
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2007.01881.x

Allograft† 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 Treg 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 (αCD154) regimen on enhanced Tregs 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, Tregs function and tolerance induction. Futhermore, 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. A long‐lived form of IL‐2/Fc reverses the blocking effects of cyclosporine on antigen‐induced cell death of alloreactive T effector cells and promotes graft survival in an islet allograft model.