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

Abstract

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.

Immunological and histological evaluation of clinical samples from psoriasis patients treated with anti-CD6 itolizumab

“…68 In our study, patients had serum concentrations of IL-10 similar to those described in previous works. 61,69 Itolizumab treatment did not have a clear effect on IL-10 modulation. Nevertheless, increased serum levels were observed at the end of the scheme, likely because higher itolizumab dose was administered during the entire schedule.…”

“…60 IL-10 inhibits pro-inflammatory cytokine production by activated T lymphocytes, but treatment of psoriasis patients with recombinant human IL-10 failed to induce an overall anti-inflammatory response. 61 The expression levels of this cytokine in the lesions and the changes in different therapeutic studies do not show a regular pattern. In a study where human recombinant IL-11, a Th2 cytokine, was administered, 62 low levels of IL-10 were observed and, as seen upon itolizumab therapy, TNF and IFN-γ levels were reduced.…”

Validation of novel multiplex technologies

“…This allows us to learn from the potential failure of drugs and to re-adapt attempts aiming to modulate the immune system more precisely [14] . Furthermore, monitoring of immunological mediators is important also for safety reasons and for the understanding/ interpretation of side effects [15] . In order to achieve a more complete picture in order to allow an adequate interpretation of data, several multiplex analysis platforms have been developed, which allow the parallel analysis of multiple analytes from small amounts of material.…”

IL-10–Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function

“…For instance, human skin mast cells have been found to be major producers of the IL-10 homolog IL-22 in psoriasis patients, leading to increased psoriatic plaques (42). One clinical study found that IL-10 therapy in psoriasis patients exacerbated inflammation and increased Th2 cytokines (9). While miR-155 expression was found to be lower among benign skin disorders (including psoriasis) than in cutaneous T cell lymphoma (43), no comparison of miR-155 expression in healthy and psoriatic skin has been published.…”

“…However, animal studies and clinical administration of IL-10 disclosed undesirable pro-inflammatory properties. Several studies of IL-10 administration in experimental endotoxemia (6) as well as studies of patients with Crohn’s disease (7), systemic lupus erythematosus (SLE) (8), and psoriasis (9) have shown immunostimulatory effects of IL-10 that correlated with disease severity.…”