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

Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response
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 ?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.
0140-6736
2149-2153
Bryan, Shannon A.
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O'Connor, Brian J.
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Matti, Salah
039c5b75-f574-4a23-b0a4-a6ff0058a2b4
Leckie, Margaret J.
daf510ac-a547-494a-b325-d9ebe89cce1b
Kanabar, Varsha
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Khan, Jamey
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Warrington, Steven J.
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Renzetti, Louis
d0ac76ca-b0bc-4257-9bf2-6ff4d38d5504
Rames, Alexis
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Bock, JuergenA.
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Boyce, Malcolm J.
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Hansel, Trevor T.
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Holgate, Stephen T.
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Barnes, Peter J.
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Bryan, Shannon A.
1290999c-e7b8-47cb-93a2-80ed51fb5af6
O'Connor, Brian J.
b1626f56-46a3-4691-a0c5-64b0e5340f0b
Matti, Salah
039c5b75-f574-4a23-b0a4-a6ff0058a2b4
Leckie, Margaret J.
daf510ac-a547-494a-b325-d9ebe89cce1b
Kanabar, Varsha
29b5bd1d-7b21-4618-897c-eae7efdad98b
Khan, Jamey
0699511a-d368-4205-af28-a94053ac64a9
Warrington, Steven J.
1366cf6b-abe4-4192-9fda-b32ed713d605
Renzetti, Louis
d0ac76ca-b0bc-4257-9bf2-6ff4d38d5504
Rames, Alexis
5451d88a-3194-4328-abef-c9e91f3577b3
Bock, JuergenA.
d29190a0-32e8-4524-bef2-3ea85d91a303
Boyce, Malcolm J.
00f9abae-d04e-4e07-b0bd-b0fce88f3b11
Hansel, Trevor T.
f8a08889-0db6-4856-9f2b-ddd5887a547a
Holgate, Stephen T.
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Barnes, Peter J.
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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).

Record type: Article

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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Published date: 2000
Organisations: Infection Inflammation & Immunity

Identifiers

Local EPrints ID: 26969
URI: https://eprints.soton.ac.uk/id/eprint/26969
ISSN: 0140-6736
PURE UUID: 447e8330-6cf0-4234-8223-2705cd447113

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Date deposited: 28 Apr 2006
Last modified: 05 Oct 2018 12:04

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Contributors

Author: Shannon A. Bryan
Author: Brian J. O'Connor
Author: Salah Matti
Author: Margaret J. Leckie
Author: Varsha Kanabar
Author: Jamey Khan
Author: Steven J. Warrington
Author: Louis Renzetti
Author: Alexis Rames
Author: JuergenA. Bock
Author: Malcolm J. Boyce
Author: Trevor T. Hansel
Author: Peter J. Barnes

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