Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis.
T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells.
Division of Rheumatology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095, USA.
Anagha A
AA
Divekar
Dinesh
D
Khanna
Fereidoun
F
Abtin
Paul
P
Maranian
Rajeev
R
Saggar
Rajan
R
Saggar
Daniel E
DE
Furst
Ram Raj
RR
Singh
D000328:Adult; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D001549:Benzamides; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000276:immunology; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015847:Interleukin-4 / Q000276:immunology*; D008168:Lung / Q000000981:diagnostic imaging / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011859:Radiography; D012595:Scleroderma, Systemic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology
D015703:Antigens, CD; D001549:Benzamides; D015815:Cell Adhesion Molecules; C483616:ICAM3 protein, human; C508598:IL4 protein, human; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015847:Interleukin-4; D000068877:Imatinib Mesylate