Therapeutic Targeting of CC Ligand 21 or CC Chemokine Receptor 7 Abrogates Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary Fibroblasts to Immunodeficient Mice

Abstract

Idiopathic interstitial pneumonias (IIPs) are a collection of pulmonary fibrotic diseases of unknown etiopathogenesis. CC chemokine receptor 7 (CCR7) is expressed in IIP biopsies and primary fibroblast lines, but its role in pulmonary fibrosis was not previously examined. To study the in vivo role of CCR7 in a novel model of pulmonary fibrosis, 1.0 x 10(6) primary fibroblasts grown from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, or histologically normal biopsies were injected intravenously into C.B-17 severe combined immunodeficiency (SCID)/beige (bg) mice. At days 35 and 63 after idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblast injection, patchy interstitial fibrosis and increased hydroxyproline were present in the lungs of immunodeficient mice. Adoptively transferred nonspecific interstitial pneumonia fibroblasts caused a more diffuse interstitial fibrosis and increased hydroxyproline levels at both times, but injected normal human fibroblasts did not induce interstitial remodeling changes in C.B-17SCID/bg mice. Systemic therapeutic immunoneutralization of either human CCR7 or CC ligand 21, its ligand, significantly attenuated the pulmonary fibrosis in groups of C.B-17SCID/bg mice that received either type of IIP fibroblasts. Thus, the present study demonstrates that pulmonary fibrosis is initiated by the intravenous introduction of primary human fibroblast lines into immunodeficient mice, and this fibrotic response is dependent on the interaction between CC ligand 21 and CCR7.

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

“…The discovery that human IPF fibroblasts generate IL-13 allowed for an in vivo study directed at the role of this cytokine in a humanized SCID model of IPF (30,42). An antibody-based approach was used in this model using a recombinant human IgG4, tralokinumab, which blocks human IL-13.…”

“…An antibody-based approach was used in this model using a recombinant human IgG4, tralokinumab, which blocks human IL-13. The administration of tralokinumab at Day 35 after the injection of human IPF fibroblasts and the establishment of fibrosis in the lungs of SCID mice (42) led to a significant reduction in quantifiable histological (i.e., reduced alveolar wall thickening, airway epithelium thickness, and basement membrane thickness), circulating (i.e., serum CC16), and lung-associated (i.e., reduced BAL caspase 3 activity) markers of lung fibrosis compared with PBS-or control IgG4-treated SCID mice that received the same IPF fibroblasts. Taken together, these data indicate that tralokinumab reduced lung fibrosis by inhibiting the profibrotic pathway evoked by IPF fibroblast-derived human IL-13 in a SCID IPF model, leading to improved lung repair.…”

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

“…The lungs were harvested 4 weeks after cell administration. Collagen content was quantified in the left-lung tissue by Sircol assay and served as the primary endpoint (48). Histological (H&E and trichrome staining) and immunohistochemical analyses were performed on paraffin-embedded and frozen right-lung tissue.…”

Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report

“…Such models will be important in helping elucidate biological changes that occur with aging that make the lung more susceptible to fibrosis. Additionally, recent advances have been made to "humanize" mouse fibrosis models using approaches such as infusion of human IPF fibroblasts into immunodeficient NOD/SCID/Beige mice (59,60 …”