Heme oxygenase-1 modulates CD62E-dependent endothelial cell-monocyte interactions and mitigates HLA-I-induced transplant vasculopathy in mice

Front Immunol. 2025 Mar 7:16:1447319. doi: 10.3389/fimmu.2025.1447319. eCollection 2025.

Abstract

The main risk factor for developing transplant vasculopathy (TV) after solid organ transplantation is de-novo production of donor-specific antibodies (DSAs) binding to endothelial cells (ECs) within the graft's vasculature. Diverse leukocyte populations recruited into the vessel wall via activated ECs contribute to vascular inflammation. Subsequent smooth muscle cell proliferation results in intima hyperplasia, the pathophysiological correlate of TV. We demonstrated that incubating aortic EC with anti-HLA-I antibodies led to increased monocyte adhesion to and transmigration across an EC monolayer. Both occurred in a CD62E-dependent fashion and were sensitive toward the anti-inflammatory enzyme heme oxygenase (HO)-1 modulation. Using a murine heterotopic aortic transplantation model, we demonstrated that anti-MHC I antibody-induced TV is ameliorated by pharmacologically induced HO-1 and the application of anti-CD62E antibodies results in a deceleration of developing TV. HO-1 modulation is a promising therapeutic approach to prevent leukocyte recruitment and subsequent intima hyperplasia in TV and thus precludes organ failure.

Keywords: accommodation; adhesion; anti-HLA-1 antibodies; chronic rejection; endothelial cells; heme oxygenase-1; monocyte transmigration; transplantation.

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Communication / immunology
  • Disease Models, Animal
  • Endothelial Cells* / immunology
  • Endothelial Cells* / metabolism
  • Heme Oxygenase-1* / metabolism
  • Humans
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Monocytes* / immunology
  • Monocytes* / metabolism
  • Vascular Diseases* / etiology
  • Vascular Diseases* / immunology
  • Vascular Diseases* / metabolism

Substances

  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Membrane Proteins

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by the German Research Foundation (LA 2343/7-1) to JL and by the Heidelberger Stiftung Chirurgie (2021/461) to LS. This research did not receive any other specific grants from funding agencies within the public, commercial, or non-profit sectors. Departmental funds were provided from the Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.