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Effects of Cyclosporine on Transplant Tolerance: The Role of IL‐2
Author(s) -
Kang H. G.,
Zhang D.,
Degauque N.,
Mariat C.,
Alexopoulos S.,
Zheng X. X.
Publication year - 2007
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2007.01881.x
Subject(s) - medicine , immunology , cd154 , immune tolerance , alemtuzumab , monoclonal antibody , blockade , transplantation , immune system , cytotoxic t cell , antibody , receptor , cd40 , biology , in vitro , biochemistry
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 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 (αCD154) 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. 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.