DIFFERENTIAL IMMUNO-SUPPRESSIVE EFFECTS OF METABOLIC-INHIBITORS ON T-LYMPHOCYTE ACTIVATION

An important challenge in the field of auto-immune diseases, bone marr ow and organ transplantation is the control of T-lymphocyte activation . To gain more insight into the in vitro correlation of immunosuppress ion, we investigated the effects of cyclosporin A (CSA) and two other metabolic inhibitors on cytokine secretion and T-cell proliferation . Secretion of TNF-alpha and GM-CSF was much more resistant to metabolic inhibitors than proliferation or synthesis of IL-1alpha or IL-2 . Mor eover, our data suggested that the regulation of IL-1alpha production in T-cells was CSA and protein kinase C (PKC)-dependent, as opposed to monocytes regulation. The receptivity to the epithelial cell-derived cytokine IL-7, associated either with antigen-dependent or independent triggering, was almost similarly inhibited by cyclosporin A, forskoli n or PKC inhibitor, in sharp contrast to IL-2 receptivity. In this lat ter case, CD28 + IL-2 stimulation was more sensitive to both forskolin and PKC inhibition than that of CD2 or CD3 + IL-2. With regard to CSA effects, limiting dilution analysis provided evidence for some hetero geneity at the clonal level. This strongly suggested that T-cell funct ional monitoring at the population level does not truly reflect the ac tual immunosuppression. Additional experiments are required to evaluat e the sensitivity to metabolic inhibitors of T-lymphocyte activation v ia the natural ligands of CD2 and CD28.