Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant repair that diminishes lung function via mechanisms that remain poorly understood. CC chemokine receptor (CCR10) and its ligand CCL28 were both elevated in IPF compared with normal donors. CCR10 was highly expressed by various cells from IPF lungs, most notably stage-specific embryonic antigen-4–positive mesenchymal progenitor cells (MPCs). In vitro, CCL28 promoted the proliferation of CCR10+ MPCs while CRISPR/Cas9–mediated targeting of CCR10 resulted in the death of MPCs. Following the intravenous injection of various cells from IPF lungs into immunodeficient (NOD/SCID-γ, NSG) mice, human CCR10+ cells initiated and maintained fibrosis in NSG mice. Eph receptor A3 (EphA3) was among the highest expressed receptor tyrosine kinases detected on IPF CCR10+ cells. Ifabotuzumab-targeted killing of EphA3+ cells significantly reduced the numbers of CCR10+ cells and ameliorated pulmonary fibrosis in humanized NSG mice. Thus, human CCR10+ cells promote pulmonary fibrosis, and EphA3 mAb–directed elimination of these cells inhibits lung fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic and progressive scarring of the lungs associated with inexorable decline in lung function
We noted that neither KB243 nor KB004 treatments in humanized NOD Cg-PrkdcSCID IL2rgTm1wilSzi (NSG) mice evoked inflammation in the mouse lung based upon findings from a Bioplex analysis for murine IL-2, IL-10, IL-12-p70, and TNF-α (Supplemental Figure 10, A–E) in the bronchoalveolar lavage (BAL) from naive and humanized mice. These results demonstrate that KB004-directed targeting of CCR10+ IPF cells in humanized NSG mice was less efficacious therapeutically compared with its effects preventatively, possibly due to the loss of immune effector cells with time in this NSG mouse model of lung fibrosis
The transcript and protein expression of this receptor was highest in IPF lungs from patients who experienced rapid progression over the first year after diagnosis compared with IPF patients showing slow or stable disease and normal donors
Summary
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic and progressive scarring of the lungs associated with inexorable decline in lung function. It is one of the most aggressive forms of interstitial pneumonias, with a median time of survival of 3–5 years after diagnosis [1]. The links between genetics and environment in IPF have been extensively investigated [3–7] None of these studies have consistently identified a causative agent(s) in IPF, thereby making it difficult to accurately model and validate novel therapeutics in this disease. Research efforts have been directed at cell-mediated pathways, which are not targeted by these drugs and might contribute to IPF progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
