PDCs and IL-4+ T-cells in scleroderma as novel targets of imatinib mesylate (44.18)

Abstract

Abstract Fibrosis is the end-result of many inflammatory conditions. Using scleroderma-associated interstitial lung disease (SLD) as a model fibrotic disease, we investigated cellular mediators of fibrosis in an open-label trial of imatinib mesylate (imatinib), a tyrosine kinase inhibitor. At baseline, high-resolution computer tomography (HRCT) findings of SLD strongly correlated with plasmacytoid dendritic cells (pDC) and IL-4-producing (IL-4+) T-cells in bronchoalveolar lavage (BAL) from individual lung lobes. pDC and IL-4+ and CD4+ T-cells in BAL correlated with each other, and with molecules CCL24, Nampt, PAI1-active, and PDGF-AB, which can recruit/activate leukocytes, smooth muscle cells and collagen-producing cells. pDCs also correlated with IL-3 and M-CSF. One-year post-imatinib, lung pDC and IL-4+ T-cells were significantly reduced. Interestingly, CD4+ T-cells increased along with soluble ICAM-3 and PECAM-1, except in one patient who showed worsened SLD. Thus we envision a role for pDCs in SLD, and propose that IL-3/M-CSF induce differentiation and maturation of pDCs that mediate local T-cell infiltration and differentiation into IL-4+ T-cells and promote fibrosis. Further elucidation of this axis and how drugs such as imatinib intercept it may identify targets to counter fibrosis that invariably leads to end-organ failure.