Effect of interleukin 2 on the immunosuppressive action of cyclosporine.
The influence of exogenous interleukin 2 (IL-2) on the immunosuppressive effect of cyclosporine in the mixed lymphocyte response (MLR) was examined. Results show that addition of exogenous IL-2 to a MLR containing graded doses of CsA (0.01-2.5 micrograms/ml) restored a normal proliferative response to alloantigens. In contrast, the effect of exogenous IL-2 on the induction of cytotoxic lymphocytes in primary MLR in the presence of CsA was variable. At the highest doses of CsA (0.5-2.5 micrograms/ml), no cytotoxic T cell activity could be detected, regardless of the presence of exogenous IL-2. However, at a lower dose of CsA (0.1 microgram/ml) that routinely resulted in the total inhibition of cytotoxic T cell induction, addition of exogenous IL-2 resulted in significant levels of detectable cytotoxic T cell activity. The effect of time-sequential addition of CsA or CsA-plus-exogenous-IL-2 on the proliferative and CML responses in MLR was also examined. Results show that addition of CsA to ongoing primary MLR cultures within the first 48-96 hr of culture results in the significant inhibition of the proliferative and CML response in MLR. Addition of CsA-plus-exogenous-IL-2 to ongoing cultures resulted in no significant inhibition of the proliferative response. In contrast, addition of CsA-plus-exogenous-IL-2 within the first 4 hr of culture did not overcome the immunosuppressive effect of CsA. At 18 hr of culture addition of CsA resulted in complete suppression of the CML response, whereas the addition of CsA-plus-IL-2 resulted in significant levels of cytotoxicity. Thereafter addition of CsA-plus-IL-2 resulted in enhanced levels of cytotoxic T cell activity compared with cultures receiving CsA alone. Taken together, our results suggest that: (1) exogenous IL-2 can overcome the immunosuppressive effect of CsA on the proliferative response in MLR to alloantigens; (2) at high levels of CsA, IL-2 cannot overcome the immunosuppressive effect of CsA on the induction of cytotoxic T-lymphocytes; (3) there are doses of CsA at least in vitro, that allow for the activation of the cytotoxic T cell, presumably with the acquisition of a receptor for IL-2 but without the clonal amplification due to inhibition of IL-2 production; and (4) time-sequential studies revealed that the development of responsiveness to IL-2 by the precursor cytotoxic T cell occurs 4-18 hr after exposure to the stimulating alloantigen with clonal expansion if IL-2 is present.
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D000818:Animals; D003524:Cyclosporins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D006922:Hylobates; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000502:physiology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D011971:Receptors, Immunologic / Q000032:analysis; D015375:Receptors, Interleukin-2; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D003524:Cyclosporins; D007376:Interleukin-2; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2