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

Lancet. 2000 Dec 23-30;356(9248):2149-53. 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 microg/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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use*
  • Adult
  • Analysis of Variance
  • Asthma / drug therapy*
  • Bronchial Provocation Tests
  • Double-Blind Method
  • Eosinophils / drug effects
  • Eosinophils / metabolism*
  • Female
  • Histamine / blood
  • Humans
  • Interleukin-12 / therapeutic use*
  • Leukocyte Count
  • Male
  • Recombinant Proteins / therapeutic use*
  • Sputum / cytology
  • T-Lymphocytes, Helper-Inducer / drug effects

Substances

  • Adjuvants, Immunologic
  • Recombinant Proteins
  • Interleukin-12
  • Histamine