Regulation of antigen-induced human T-lymphocyte responses by calcineurin antagonists

Background: Cyclosporin A (CS) and tacrolimus (FK506, FK) are calcineurin antagonists used widely as T-cell immunosuppressants: however, their relative efficacy on antigen-stimulated T-cell subsets remains undefined. Objective: We have examined the effects of CS and FK on antigen-driven proliferation and cytokine generation from human PBMCs and T-cell clones, Methods: Proliferation was assessed by tritiated thymidine incorporation. Cytokine generation was assessed by reverse transcription-PCR and ELISA, Results: Ragweed- and tetanus toroid-driven proliferation of PBMCs was down-regulated equally by CS or FK, Gene expression for proinflammatory cytokines (IL-I, IL-5, IL-13, and IFN-gamma) assessed by reverse transcription-PCR was down-regulated in a concentration-dependent manner by either drug. Antigen-induced proliferation of ragweed-specific Th0, Th1, or Th2 clones was inhibited by either CS or FK. Cytokine gene expression and protein secretion into culture supernatants (IL-4, IL-5, IL-13, and IFN-gamma) were down-regulated in a concentration-dependent manner by either CS or FK in all relevant T-cell subsets. Interestingly, down-regulation of IL-5 protein generation from Th0 and Th2 clones was consistently less sensitive to either drug than was the effect on either IL-4 or IL-13 protein generation, Conclusion: CS and FK promote equivalent down-regulation of Th0, Th1, and Th2 responses; how ever, IL-5 generation is relatively insensitive to the immunomodulatory effects of calcineurin antagonists.