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


RESULTS
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.


CONCLUSIONS
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.
Bryan
S A
SA
National Heart and Lung Institute, Imperial College, London, UK.
O'Connor
B J
BJ
Matti
S
S
Leckie
M J
MJ
Kanabar
V
V
Khan
J
J
Warrington
S J
SJ
Renzetti
L
L
Rames
A
A
Bock
J A
JA
Boyce
M J
MJ
Hansel
T T
TT
Holgate
S T
ST
Barnes
P J
PJ
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000704:Analysis of Variance; D001249:Asthma / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D004311:Double-Blind Method; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006632:Histamine / Q000097:blood; D006801:Humans; D018664:Interleukin-12 / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013183:Sputum / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects
D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D018664:Interleukin-12; D006632:Histamine