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 1

CCR10 expression in normal and IPF lungs.

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CCR10 expression in normal and IPF lungs. (A) Transcriptomic analysis of...
(A) Transcriptomic analysis of lung samples (normal and rapid- and slow-IPF) for CCR10 transcripts. Data shown are mean ± SEM; n = 3–9/group. *P ≤ 0.05 via 1-way ANOVA with Tukey’s multiple comparisons test. (B) Analysis of peripheral blood CCL28 transcript expression and progression-free survival, as defined by death or 10% forced vital capacity (FVC) decline in 67 IPF patients over 24 months. (C–L) IHC analysis for CCR10 protein expression in normal lung explants (C and D), slow-IPF (E and F) and rapid-IPF lung biopsies (G and H), and IPF lung explants (I and J). Shown are representative images acquired at original magnification 50× (top) and 200× (bottom). The corresponding IgG isotype control staining is shown in the inlaid images. n = 3–15 lung samples/group. (K–M) Flow cytometric analysis of cultured fibroblasts from normal and IPF lung explants for cell surface CCR10 protein. Representative dot plots of CCR10 expression (K), average percentage of fibroblasts expressing CCR10 (L), and the geometric mean fluorescence intensity (GMFI) of CCR10 expression (M) on fibroblasts from normal (n = 6) and IPF (n = 7) lung explants. Data shown are mean ± SEM; *P ≤ 0.05 via 2-tailed Mann-Whitney nonparametric test.