Effect of cyclosporin A on human lymphocyte responses in vitro. IV. Production of T cell stimulatory growth factors and development of responsiveness to these growth factors in CsA-treated primary MLR cultures.

Abstract Cyclosporin A (CsA) was assessed for its effect on the production of T lymphocyte stimulating growth factors and the development of responsiveness to these growth factors in primary MLR. CsA at tolerizing doses (2.5, 1.0, and 0.5 µg/ml) markedly reduced, but did not abolish, the production of T lymphocyte growth factors, which were found to be at highest concentration in day 2 supernatants from control and CsA treated MLR cultures. The reduced level of the growth factors was not due to the presence of a soluble inhibitor. In addition, CsA did not inhibit the response of primed lymphocytes from control cultures to these growth factors. The acquisition of responsiveness to the T lymphocyte stimulatory factors in CsA-treated cultures showed a clear dichotomy between lymphocyte subpopulations detected in functional assays. On the one hand, primed lymphocytes from CsA-tolerized cultures upon exposure to the growth factors exhibited a proliferative response that was associated with a two- to five-fold increase in suppressor cell activity. In contrast, no CML response to these stimulatory factors was detected in alloantigen-primed cells from CsA-tolerized cultures, whereas cells from control MLR cultures or MLR cultured with low levels of CsA exhibited a strong CML response. Removal of a nylon wool-adherent suppressor did not restore the ability of the CsA-tolerized cells to generate a CML response upon stimulation with the T lymphocyte stimulatory growth factors but reestablished the capacity to generate cytotoxic T cells when challenged with the sensitizing alloantigen. These results suggest that the precursor cytotoxic T cell in CsA-treated MLR cultures do not acquire the ability to respond to T cell growth factors, thus retaining their immunologic naivete, whereas suppressor cells in these cultures do become activated, and their activity is enhanced by these stimulatory growth factors.