Interleukin-12: Basic Principles and Clinical Applications

Abstract

The most important advance in the last 10 years in our understanding of how to direct the immune response by vaccination or immunotherapy has been the description and subsequent refinement of the T helper type 1/2 (Th 1/2) paradigm. (Mosmann and Coffman 1989). This paradigm has provided the framework necessary to formulate basic questions related to defining the cues pathogens provide that shape the immune response. A major advance in this area came with the discovery of interleukin-12 (IL-12) (Kobayashi et al. 1989; Stern et al. 1990) and the subsequent demonstration that IL-12 promotes the development of Th 1 cells in vitro (Hsieh et al. 1993; Manetti et al. 1993). Thus, in naive T cell populations exposure to antigen in the presence of IL-12 for several days, followed by restimulation with antigen alone, led to the development of interferon (IFN)-γ producing T cells. Moreover, it was found that one could link together IL-12, the innate immune response, pathogens, and Th 1 cell development. This was done by showing that bacteria, such as Listeria monocytogenes, induced Th l cell development and that this occurred by stimulation of macrophages to produce IL-12 (D’Andrea et al. 1992; Hsieh et al. 1993). This observation has led to the description of a common pathway leading from the innate immune response to adaptive immunity, in which intracellular pathogens stimulate macrophages to produce IL-12, which promotes the development of Th 1 cells from a naive cell population. This pathway can now be exploited to develop approaches for the design of new immunotherapies and vaccines.