Effects of cyclosporine on transplant tolerance: the role of IL-2.
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.
Kang
H G
HG
Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Zhang
D
D
Degauque
N
N
Mariat
C
C
Alexopoulos
S
S
Zheng
X X
XX
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D023201:CD40 Ligand / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000627:therapeutic use*; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D000071821:Dystonin; D015870:Gene Expression / Q000187:drug effects*; D006084:Graft Rejection / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007376:Interleukin-2 / Q000235:genetics*; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012313:RNA / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C095667:Dst protein, mouse; D000071821:Dystonin; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; D023201:CD40 Ligand; D012313:RNA; D016572:Cyclosporine