A number of macrophage-derived cytokines, including IL-1 and TNF-alpha, have been found to regulate the functional activities of human T cells. Like IL-1 and TNF-a, IL-12 potentiates certain T cell effector functions, particularly anti-tumor activities. Although it is well known that IL-12 amplifies IFN-gamma synthesis in activated T cells, its potential effects on production of other T cell-derived cytokines are not well defined. In this project, we are evaluating the effects of IL-12 on expression of multiple cytokines, including IFN-g, IL-2, TNF-a and IL-10. By defining exactly which cytokines are induced by IL-12 stimulation in human T cells, we will gain a greater understanding of the biological activities of this potent cytokine. This information may be useful when evaluating any therapeutic activity observed in future clinical trials. It may also provide clues to the physiological basis for certain toxicities associated with high dose IL-12 therapy. Interleukin-12 (IL-12) is a relatively recently discovered cytokine that amplifies production of IFN-gamma in activated T cells and NK cells. At present, relatively little is known about the effects of IL-12 on expression of other T cell-derived cytokines. IL-12 is currently being tested as a potential therapeutic agent for the treatment of a number of diseases, including cancer and HIV infection. It is also being tested as an adjuvant with certain microbial vaccines. Characterization of the effects of IL-12 on cytokine expression in human T cells may provide important information regarding the mechanism(s) by which this cytokine potentiates various immune effector functions in vivo. It may also help CBER staff to more critically evaluate future clinical trials of IL-12. Furthermore, analysis of the effects of IL-12 on cytokine expression in vitro may identify surrogate markers of IL-12 activity that may be useful in monitoring the potency of recombinant IL-12 in human recipients.
