Targeting the Human βc Receptor Inhibits Contact Dermatitis in a Transgenic Mouse Model

Kwok Ho Yip, Duncan McKenzie, Hayley S. Ramshaw, Jessica Chao, Barbara J. McClure, Elmar Raquet, Timo Kraushaar, Joachim Röder, Mhairi Maxwell, Monther Alhamdoosh, Andrew Hammet, Jia Hong Fong, Kathleen Zeglinski, Katherine Monaghan, Harshita Pant, Michele A. Grimbaldeston, Gino Vairo, Nicholas J. Wilson, Catherine M. Owczarek, Timothy R. HercusAngel F. Lopez, Damon J. Tumes

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The beta common (βc) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit βc, a property that has made βc an attractive target to simultaneously inhibit these cytokines. However, the species specificity of βc has precluded testing of inhibitors of human βc in mouse models. To overcome this problem, we developed a human βc receptor transgenic mouse strain with a hematopoietic cell‒specific expression of human βc instead of mouse βc. Human βc receptor transgenic cells responded to mouse GM-CSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of ACD. Similarly, Il3–/– mice developed ACD pathology comparable with that of wild-type mice. Importantly, the blocking anti–human βc antibody CSL311 strongly suppressed ear pinna thickening and histopathological changes typical of ACD and reduced accumulation of neutrophils, mast cells, and eosinophils in the skin. These results show that GM-CSF and IL-5 but not IL-3 are major mediators of ACD and define the human βc receptor transgenic mouse as a unique platform to test the inhibitors of βc in vivo.

Original languageEnglish
Pages (from-to)1103-1113.e11
JournalJournal of Investigative Dermatology
Volume142
Issue number4
DOIs
Publication statusPublished or Issued - Apr 2022
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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