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 microg/kg/day or 20 microg/kg/3 x/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-beta1). 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.
SummaryInterleukin (IL)-10 is one of the most crucial immunoregulatory cytokines. Its short-term effects have been analysed extensively, but little is known about its long-term effects. This is of considerable importance, as high systemic IL-10 levels are present for long periods in patients with persistent viral infections, certain cancers and in critical care patients. Our study investigated the effects of the long-term presence of IL-10 on human peripheral blood monocytes. In vitro, IL-10 treatment of these cells for 7 days induced the development of a novel cell type characterized by unique phenotypical and functional characteristics. These cells showed high HLA-DR expression and low expression of CD86 and other co-stimulatory molecules on their surface. The mRNA levels of both HLA-DR and CD86 were high, but no intracellular accumulation of CD86 protein was observed. With respect to its function, these cells showed strongly diminished tumour necrosis factor-a production following lipopolysaccharide stimulation, strongly diminished allogenic CD4 + T cell stimulatory capacity, and even induced a hyporesponsive state in CD4 + T cells. The phenotype remained stable despite the removal of IL-10. In vivo, we found monocytic cells from patients exhibiting this phenotype after longterm IL-10 exposure. These results complement our knowledge further about the biological effects of IL-10 and may provide an explanation for the sustained immunodeficiency in cases of the persistent presence of systemic IL-10.
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