Effect of cyclosporin A on T cell immunity. I. Dose-dependent suppression of different murine T helper cell pathways

Cyclosporin A (CsA) is used as a clinical immunosuppressive agent. Despite its immunosuppressive potential, some studies involving in vivo administration of cyclosporin have failed to verify the immunosuppressive activity of this agent. The present study investigates the effect of different concentrations of CsA added in vitro, or of different doses of CsA administered in vivo, on the ability of murine spleen cells to produce interleukin 2 and to generate cytotoxic T lymphocytes in vitro when stimulated with TNP-self or H-2 alloantigens. The results indicate that self Ia-restricted T helper (Th) cells are more sensitive to lower doses of CsA than Th cells that are allorestricted. Thus, doses of CsA were found (15-30 mg/kg) that inactivated self Ia-restricted Th function, but not other Th or effector function. This Th cell defect could be partially corrected in vitro by addition of Th cell factors to the sensitization cultures. A higher dose (75 mg/kg) of CsA inactivated all detectable T cell responses, and this defect was not corrected by addition of Th cell factors. T cell function returned to normal levels within two weeks of cessation of CsA at all three doses of CsA tested. The selective loss of L3T4 Th function at the lower doses of CsA was associated with a radiosensitive, Ly-2 suppressor T cell that was selective in its action on self Ia-restricted Th cell function. Loss of all T cell function at the higher dose of CsA was associated with a radioresistant non-T suppressor cell that inactivated all T cell function tested. These results are discussed with respect to the selective dose-dependent effects of CsA on Th subsets, on the activation of suppressor cells with similar selectivity, and the implications of these findings on the use of CsA to prevent rejection of tissue allografts.