Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response

Bryan, Shannon A., O'Connor, Brian J., Matti, Salah, Leckie, Margaret J., Kanabar, Varsha, Khan, Jamey, Warrington, Steven J., Renzetti, Louis, Rames, Alexis, Bock, JuergenA., Boyce, Malcolm J., Hansel, Trevor T., Holgate, Stephen T. and Barnes, Peter J. (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. The Lancet, 356 (9248), 2149-2153. (doi:10.1016/S0140-6736(00)03497-8).

Abstract

Background: Interleukin-12 (IL-12) is a macrophage-derived cytokine that modulates T lymphocyte responses and has the capacity to suppress allergic and eosinophilic inflammation.
Methods: We carried out a double-blind, randomised, parallel group clinical study, in which patients with mild allergic asthma were given subcutaneous recombinant human IL-12 at increasing weekly injections of 0·1, 0·25, 0·5 ?g/kg (n=19), or placebo (n=20). We compared responses to inhaled allergen challenge 24 h before the first injection and 24 h after the final injection. Airways hyper-responsiveness and concentrations of peripheral blood eosinophils and sputum eosinophils were also assessed.
Findings: IL-12 caused a significant decrease from baseline in the main peripheral blood eosinophil count 24 h after the fourth injection compared with placebo (p=0·0001). Sputum eosinophils were also significantly decreased 24 h after allergen challenge when treated with IL-12 compared with placebo (p=0·024). IL-12 caused a non-significant trend towards improvement in airway hyper-responsiveness to histamine, but had no significant effect on the late asthmatic reaction after inhaled allergen challenge. After administration of IL-12, four of 19 patients withdrew prematurely; two with cardiac arrhythmias, one with abnormal liver function, and a single patient with severe flu-like symptoms.
Interpretation: We have shown that IL-12 lowers numbers of blood and sputum eosinophils, but without any significant effects on airway hyper-responsiveness or the late asthmatic reaction. This questions the role of eosinophils in mediating these reactions, and has important implications for development of new anti-inflammatory treatments.

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