Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers*

Abstract

Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 micrograms/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 micrograms/kg (five of six subjects had mild flu-like syndrome). Mean serum interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human interleukin-10 significantly suppressed production of the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.

Koi Herpesvirus Encodes and Expresses a Functional Interleukin-10

“…Our data confirm that IL-10R1 is functional during embryonic development in response to its cognate ligand, causing an increase in leukocytes. Similarly, drIL-10 overexpression also causes an increase in leukocytes, which is consistent with its role in other systems (7,21). Importantly, we have shown that khvIL-10 could also increase leukocyte numbers in this heterologous setting, acting via the IL-10 receptor subunit, IL-10R1.…”

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

“…When administered to pregnant rhesus monkeys, this cytokine gains access to the amniotic cavity where it harbors with a half-life of 13.2 hours [65], which is higher than the half-life of 2-4 hours in the circulation of volunteers following subcutaneous administration [210]. The longer half-life of IL-10 within the amniotic cavity indicates that the amniotic cavity may provide a depot-like effect prolonging the effectiveness of the treatment [65].…”

“…Clinical trials in which IL-10 was administrated systemically to healthy volunteers have demonstrated that, at doses associated with biological activities, this cytokine has minimal side effects [209][210][211][212][213], including a mild flu-like syndrome [210], transient mild to moderate neutrophilia, monocytosis, lymphopenia (dramatic reductions of 40-70% in circulating lymphocytes expressing the T cell markers CD2, CD3, and CD7), and a delayed decrease of platelet count [209,210]. Thus, IL-10 has been proposed as a candidate for treatment of bacterial sepsis, and more generally as an effective anti-inflammatory agent [72] and clinical trials have shown that its systemic administration is followed by modest but significant improvement of psoriasis [214,215], Crohn's disease [216], rheumatoid arthritis [217], and chronic hepatitis C infection [218].…”

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

“…Disease-associated proinflammatory cytokines such as TNF-a, IL-1b, IL-12, and IL-17 were reduced by half in some studies, indicating a pharmacodynamic activity (43). However, the suppression of IL-1 and TNF-a lasted only as long as the serum concentration of IL-10 was sufficiently elevated, returning to high values 24 hours after the IL-10 injection (44). Nevertheless, in early clinical studies encouraging efficacy of IL-10 was observed in psoriasis, hepatitis, and Crohn disease.…”