Combination Cytokine Therapy

Cytokines represent a diverse group of small, soluble polypeptides that are involved in regulating a wide range of physiologic processes, including inflammation, tissue repair, and immunity. The expanding role of cytokines in these processes and the identification of over 100 putative cytokine family members have made it difficult to easily classify cytokines based on structure or function. In addition, many cytokines exhibit a variety of biologic activities and these effects may be dependent on the concentration, timing, and duration of target cell exposure to a given cytokine, as well as the influence of other cytokine and growth factors in the local microenvironment. In fact, much of the early characterization of cytokines was based on simple in vitro experiments, which have failed to accurately predict the activity of cytokines in vivo. More recent investigation using targeted knockout mice and analysis of cytokine signaling pathways is leading to new insights into the biology of many cytokines. This is perhaps best exemplified by interleukin-2 (IL-2), originally described as a T-cell growth factor and defined by its ability to induce T-cell proliferation in vitro. Such ex vivo studies predicted that IL-2 would function to promote cellular immunity through expansion of naive T-cell populations in vivo. The availability of IL-2 and IL-2 receptor knockout mice, however, demonstrated that in the absence of IL-2 signaling T-cell proliferation was increased, significant lymphadenopathy occurred, and animals succumb to aggressive autoimmune disease. This unexpected result suggests that IL-2 may actually function in vivo, not as a T-cell stimulant, but rather as a regulatory cytokine maintaining peripheral tolerance through balancing effector and regulatory T-cell pools (1).