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The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma

¹ Dept of Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, London, ² SmithKline Beecham Pharmaceuticals, Harlow, Essex, ³ The London Chest Hospital, London, UK

CORRESPONDENCE: A.B. Kay, Dept of Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK. Fax: 44 207376 3138

Keywords: Anti-CD4, asthma, cytokine, flow-cytometry, monoclonal antibody, proliferation

Received: July 14, 2000
Accepted March 12, 2001

This study was funded by SmithKline Beecham Pharmaceuticals.

CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics.

Three cohorts of patients (termed C_0.5: n=6, C_1.5: n=5, and C_3.0: n=5) received a single infusion of 0.5, 1.5 or 3.0 mg·kg^–1, respectively, with a fourth receiving placebo (C_pl: n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab's in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated.

There was a significant increase in lung function (peak expiratory flow rate) in the C_3.0 group. Following infusion in C_0.5, C_1.5 and C_3.0 but not C_pl: 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody.

Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.