THE REGULATION AND BIOLOGICAL-ACTIVITY OF INTERLEUKIN-12

Interleukin 12 (IL-12) is a pleiotropic cytokine and mediates several biological activities on human T and natural killer (NK) cells, includ ing induction of IFN-gamma production, enhancement of cell-mediated cy totoxicity and comitogenic effects on resting T-cells. The major cellu lar sources producing IL-12 are antigen-stimulated monocytes, macropha ges, and B-cells isolated from peripheral blood mononuclear cells (PBM C). Our laboratory has investigated the regulation of IL-12 gene expre ssion in both cord blood and adult PBMC, and the effects of IL-12 on i nduction of IFN-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. IL-12 mRNA expression and protein production in LP S-stimulated cord blood MNC were 3-4 fold decreased when compared with adult PBMC. There were no differences between cord blood and adult PB MC in both basal levels of transcription or the degree of transcriptio nal activation of the IL-12 gene. Additionally, the half-life of IL-12 p40 mRNA was 3-fold lower in activated cord blood compared to adult P BMC. Exogenous IL-12 induced a significant increase of IFN-gamma from both cord and adult PBMC. Cord MNC has significantly reduced levels of NK activity, and IL-12 significantly enhanced cord blood NK cytotoxic ity upto similar levels in adult PBMC. IL-12 also significantly enhanc ed cord blood NK and LAK activities against a broad range of neuroblas toma, leukemia, and lymphoma cell lines. Lower doses of IL-12 and IL-1 5 concomitantly generated either synergistic or additive effects on co rd blood NK and LAK cytotoxicities. In light of the important biologic al functions of IL-12, reduced expression and production of IL-12 from activated cord blood may contribute to the immaturity of cord blood c ellular immunity and contribute, in part, to decreased severe graft vs , host disease following unrelated cord blood stem cell transplantatio n. IL-12 enhancement of IFN-gamma, NK, and LAK activity in activated c ord blood MNC upto comparable levels in adult PBMC suggests that exoge nous IL-12 stimulation can compensate for the immaturity in cord blood cellular immunity. These characteristics of IL-12 biological activity strongly suggest its potential usefulness in future cancer immunother apy.