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 6

IPF lung cells promote fibrosis in the lungs of NSG mice.

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IPF lung cells promote fibrosis in the lungs of NSG mice. (A–C) Represen...
(A–C) Representative images of Masson’s trichrome staining of nonhumanized NSG lung (A) and humanized NSG lungs (B and C) at day 63 after intravenous injection of IPF cells. Images were acquired at original magnification 50× (top) and 200× (bottom). Blue color depicts stained collagenous regions. n = 5/group. (D) Hydroxyproline in humanized and nonhumanized NSG lungs. **P < 0.01 via 2-tailed Mann-Whitney nonparametric test. (E) Sixty-three days after IPF cell injection, lungs from NSG-GFP mice were stained in red for GFP protein. Representative image showing both the GFP+ cells (i.e., mouse) and the GFP– cells (i.e., introduced human) is shown at original magnification 200×. (F–H) NSG-GFP lungs were analyzed by flow cytometry. Shown is the average number of GFP– cells, expressing human CD45, CCR10, EpCAM, and/or PDGFRα proteins in humanized (IPF; black) relative to nonhumanized mice (naive; white). (I) Shown is the average percentage of CD45+CCR10+ and Lin–CCR10+ expressing EphA3. Data shown are mean ± SEM; n = 4–5/group. *P ≤ 0.05 via 2-tailed Mann-Whitney nonparametric test. (J–M) CCR10+ IPF lung cells were sorted and injected intravenously into NSG mice (J), and depicted are correlation analyses of hydroxyproline and number of human CD45+CCR10+ (K), EpCAM+CCR10+ (L), and Lin–CCR10+ (M) cells in NSG lungs at day 35 after cell injection. n = 5/group. Pearson’s correlation coefficient with P values indicated.