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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 2

EphA3 expression by fibroblasts and CCR10+ cells in normal and IPF lung explants.

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EphA3 expression by fibroblasts and CCR10+ cells in normal and IPF lung ...
(A–H) Flow cytometric analysis of cultured lung fibroblasts from normal and IPF patients for cell surface expression of EphA3, CCR10, stage-specific embryonic antigen-4 (SSEA4), and PDGFRα. Representative dot plot (A) and respective percentage of EphA3+ cells (B) and GMFI of EphA3 (C). Representative dot plots (D) and respective quantitation of percentage of EphA3+ (Alexa Fluor 594) cells (E) and GMFI of EphA3 (F) within gated PDGFRα+ (PE/Cy7) cells. Percentage of CCR10+EphA3+ cells (G) and CCR10+ within gated EphA3+ cells (H). Data shown are mean ± SEM; n = 4–6/group; *P ≤ 0.05, **P ≤ 0.01, or ***P ≤ 0.005 via 2-tailed Mann-Whitney nonparametric test. (I–Q) Representative immunofluorescence images showing CCR10 (green; I, L, and O), EphA3 (red; J, M, and P), and a merged composite (K, N, and Q) in normal (I–K) and IPF (L–Q) lung explants. n = 5–7/group. White arrowheads highlight cells where colocalization is observed. (R–V) Representative IHC images stained for CCR10 (red) and EphA3 (brown) in normal lung (R), IPF lung biopsies (S and T), and IPF lung explants (U and V) taken at original magnification 50× (top) and 200× (bottom). The respective IgG isotype control staining is shown in the inlaid images. n = 5–8/group.

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