Comprehensive biomarker monitoring in cytokine therapy: heterogeneous, time-dependent, and persisting immune effects of interleukin-10 application in psoriasis

Cytokine and anticytokine treatments represent promising approaches for therapy of immune-mediated diseases. In humans, however, regulatory consequences of interference with the cytokine network are only partially understood. Biomarker analysis in clinical studies may help to overcome this complexity and provide novel information about the in vivo relevance of individual cytokines. We report systemic immunological effects of IL-10 therapy in 10 psoriasis patients during a 7-week treatment period followed by a 7-week observation period. IL-10 was given s.c. at 8 mu g/kg/day or 20 mu g/kg/3x/week, and a broad range of immunological biomarkers was analyzed in an extended kinetics (17 time-points) before, during, and after IL-10 therapy. Besides the expected anti-inflammatory effects (e. g., inhibition of LPS-induced cytokine secretion), we found unexpected effects, such as activation of NK cells and an increase in parameters indicating proinflammatory activity (C-reactive protein and soluble IL-2R). Furthermore, cumulative effects (IgE and IgA), loss of effect (IL-1R antagonist and IFN-gamma secretion), or counter-regulation during and rebound after IL-10 therapy (TNF-alpha and IL-12/IL-23 p40) were found. Remarkably, some alterations were retained long after the 7-week treatment period (IL-4 secretion, monocytic CD86, and TGF-beta 1). In summary, we found manifold effects of IL-10 far beyond the immediate anti-inflammatory activity considered initially. These findings may explain the rather disappointing clinical effects of IL-10 therapy in exacerbated inflammation but also hint to its role for sustained immunological reshaping. They further exemplify the importance of analyzing an extended kinetics of an entire panel of biomarkers for understanding the effects of therapeutic interference with the cytokine network. J. Leukoc. Biol. 85: 582-593; 2009.