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

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

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 5

CRISPR/Cas9–mediated KO of CCR10 decreases MPC markers and premature senescence of the fibroblast progeny.

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CRISPR/Cas9–mediated KO of CCR10 decreases MPC markers and premature sen...
Normal and IPF fibroblasts were infected, and Puro+ cells were first selected with puromycin; then GFP+ cells among the Puro+ cells were selected by FACS. Sorted GFP+Puro+ cells are CCR10-KO cells, and empty plasmids were used as negative control (nontarget). Transcript levels in normal (A) and IPF (B) control (white), nontarget (gray), and CCR10 KO-1 (blue) and -4 (red) fibroblasts. (C–D) Control, nontarget, and CCR10 KO-1 and -4 were plated, and proliferation and senescence-associated β-galactosidase expression were assessed. (C) Shown is percentage confluence in normal and IPF fibroblasts. (D) Representative senescence-associated β-galactosidase expression in IPF fibroblast cultures. Original magnification, 20×. Data shown are mean ± SEM; n = 3–4 fibroblast lines/group. (A–C) *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 compared with control via 1-way ANOVA test (A and B) or via 2-way ANOVA test (C) with Tukey’s multiple comparisons test.