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Antibody-mediated depletion of CCR10+EphA3+ cells ameliorates fibrosis in IPF
Miriam S. Hohmann, … , Lynne A. Murray, Cory M. Hogaboam
Miriam S. Hohmann, … , Lynne A. Murray, Cory M. Hogaboam
Published May 4, 2021
Citation Information: JCI Insight. 2021;6(11):e141061. https://doi.org/10.1172/jci.insight.141061.
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Research Article Pulmonology

Antibody-mediated depletion of CCR10+EphA3+ cells ameliorates fibrosis in IPF

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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.

Authors

Miriam S. Hohmann, David M. Habiel, Milena S. Espindola, Guanling Huang, Isabelle Jones, Rohan Narayanan, Ana Lucia Coelho, Justin M. Oldham, Imre Noth, Shwu-Fan Ma, Adrianne Kurkciyan, Jonathan L. McQualter, Gianni Carraro, Barry Stripp, Peter Chen, Dianhua Jiang, Paul W. Noble, William Parks, John Woronicz, Geoffrey Yarranton, Lynne A. Murray, Cory M. Hogaboam

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Figure 8

CCR10+ cells contribute to progressive fibrosis in IPF.

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CCR10+ cells contribute to progressive fibrosis in IPF.
CCR10 and its li...
CCR10 and its ligand CCL28 are elevated in the lungs of rapidly progressive IPF patients. CCR10 expression is increased in SSEA4+ MPCs from IPF lungs. The receptor tyrosine kinase EphA3 is abundantly expressed on CCR10+ cells, and these cells are increased in IPF. CCL28 is secreted by airway basal cells, AT2 cells, and senescent fibroblasts, and, in vitro, it promotes the expansion of CCR10+ MPCs (A) and progeny (B), as well as activation [i.e., increased EphA3 expression (C) and collagen secretion (D)] and senescence of their mesenchymal progeny (B). CRISPR/Cas9–mediated KO of CCR10 reduces the percentage of MPCs and CCR10+EphA3+ cells. Concomitantly, targeting this pathway reduces the proliferative capacity and promotes a senescent phenotype. In vivo, human CCR10+ IPF cells initiate and maintain fibrosis in mice. Immune cell–mediated killing of EphA3+ cells with ifabotuzumab (KB004) reduces the percentage of CCR10+EphA3+ cells, as well as CD45+CCR10+, Lin–CCR10+, and EpCAM+CCR10+ cells, and abolishes lung remodeling.

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ISSN 2379-3708

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