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Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation

Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation
Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation
The authors have investigated whether the steroid-sparing effect of methotrexate (MTX) in severe orally glucocorticoid-insensitive asthmatics may be accounted for by the ability of this drug to increase the T-cell responsiveness sensitivity to dexamethasone in vitro. In addition the authors have investigated whether low-dose MTX treatment is associated with anti-inflammatory effects in peripheral blood and the bronchial mucosa. In eight patients with severe atopic asthma, using > or =15 mg x day(-1) prednisolone, the inhibitory effect of dexamethasone on mitogen stimulated peripheral blood mononuclear cells (PBMC) in vitro was tested before and after 8 weeks of uncontrolled treatment with MTX. Endobronchial biopsies were taken before and after MTX therapy in seven subsequent patients, and analysed using immunohistochemistry. In eight patients, serum was drawn for measuring levels of free interleukin (IL)-8. The in vitro sensitivity of PBMC to dexamethasone (at 1.6 x 10(-9) and 3.2 x 10(-10) mol x L(-1)) was significantly lower in the asthmatics before treatment when compared with the control subjects (p=0.03 and =0.001) but increased significantly after MTX treatment (p=0.04 and =0.02) to normal responsiveness. This was not associated with a decrease in peripheral blood T-cell numbers or activation. Except for a significant increase in the numbers of CD3+ (p=0.04), no significant numerical changes in activated T-cells, eosinophils, or mast cells were found (p>0.05). However, MTX treatment was associated with a significant fall in serum levels of free IL-8 (p=0.03). It is hypothesized that the steroid-sparing effect of methotrexate originates from increased sensitivity of lymphocytes to the inhibitory effects of glucocorticoids. The absence of an inhibitory effect on inflammatory cells in blood and mucosa suggests that this effect is achieved by modulating cell function rather than cell number.
0903-1936
478-485
Vrugt, B
e3fd8362-3a8b-4c7c-af7d-10d8427b62a1
Wilson, Susan J.
21c6875d-6870-441b-ae7a-603562a646b8
Bron, A
e0354c49-ecc0-411b-9b75-a9c5e3dc5837
Shute, J.
315ef8d4-96b2-467a-bbe2-e9d2bad24b9c
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Aalbers, R.
d505a4b7-d33b-463e-a807-1c1a1cbb8896
Vrugt, B
e3fd8362-3a8b-4c7c-af7d-10d8427b62a1
Wilson, Susan J.
21c6875d-6870-441b-ae7a-603562a646b8
Bron, A
e0354c49-ecc0-411b-9b75-a9c5e3dc5837
Shute, J.
315ef8d4-96b2-467a-bbe2-e9d2bad24b9c
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Aalbers, R.
d505a4b7-d33b-463e-a807-1c1a1cbb8896

Vrugt, B, Wilson, Susan J., Bron, A, Shute, J., Holgate, Stephen T., Djukanovic, Ratko and Aalbers, R. (2000) Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. European Respiratory Journal, 15 (3), 478-485. (PMID:10759440)

Record type: Article

Abstract

The authors have investigated whether the steroid-sparing effect of methotrexate (MTX) in severe orally glucocorticoid-insensitive asthmatics may be accounted for by the ability of this drug to increase the T-cell responsiveness sensitivity to dexamethasone in vitro. In addition the authors have investigated whether low-dose MTX treatment is associated with anti-inflammatory effects in peripheral blood and the bronchial mucosa. In eight patients with severe atopic asthma, using > or =15 mg x day(-1) prednisolone, the inhibitory effect of dexamethasone on mitogen stimulated peripheral blood mononuclear cells (PBMC) in vitro was tested before and after 8 weeks of uncontrolled treatment with MTX. Endobronchial biopsies were taken before and after MTX therapy in seven subsequent patients, and analysed using immunohistochemistry. In eight patients, serum was drawn for measuring levels of free interleukin (IL)-8. The in vitro sensitivity of PBMC to dexamethasone (at 1.6 x 10(-9) and 3.2 x 10(-10) mol x L(-1)) was significantly lower in the asthmatics before treatment when compared with the control subjects (p=0.03 and =0.001) but increased significantly after MTX treatment (p=0.04 and =0.02) to normal responsiveness. This was not associated with a decrease in peripheral blood T-cell numbers or activation. Except for a significant increase in the numbers of CD3+ (p=0.04), no significant numerical changes in activated T-cells, eosinophils, or mast cells were found (p>0.05). However, MTX treatment was associated with a significant fall in serum levels of free IL-8 (p=0.03). It is hypothesized that the steroid-sparing effect of methotrexate originates from increased sensitivity of lymphocytes to the inhibitory effects of glucocorticoids. The absence of an inhibitory effect on inflammatory cells in blood and mucosa suggests that this effect is achieved by modulating cell function rather than cell number.

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Published date: March 2000

Identifiers

Local EPrints ID: 191003
URI: https://eprints.soton.ac.uk/id/eprint/191003
ISSN: 0903-1936
PURE UUID: 153165c1-fb3a-4a99-ae62-8abb81a2033c
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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Date deposited: 16 Jun 2011 14:13
Last modified: 13 Oct 2018 00:37

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