Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection

Am J Transplant. 2018 May;18(5):1096-1109. doi: 10.1111/ajt.14544. Epub 2017 Nov 23.

Abstract

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1-/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR.

Keywords: alloantibody; animal models: murine; basic (laboratory) research/science; cellular biology; immunosuppressant - mechanistic target of rapamycin (mTOR); immunosuppression/immune modulation; macrophage/monocyte biology; organ transplantation in general; translational research/science; vasculopathy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Communication
  • Cells, Cultured
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism*
  • Graft Rejection / etiology*
  • Graft Rejection / metabolism
  • Graft Rejection / pathology
  • Heart Transplantation / adverse effects*
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Isoantibodies / adverse effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Monocytes / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Isoantibodies
  • Intercellular Adhesion Molecule-1
  • TOR Serine-Threonine Kinases