# The role of HLA and its coreceptors in endothelial cell activation and leukocyte recruitment in antibody-mediated transplant rejection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $621,649

## Abstract

ABSTRACT
The production of donor specific HLA class I and class II antibodies is associated with development of chronic
antibody-mediated rejection (cAMR) and transplant vasculopathy (TV). Two key features of cAMR are
endothelial cell (EC) dysfunction and infiltration of immune cells, particularly macrophages. The proposed
research will explore the novel paradigm that antibody crosslinking of HLA class I with ITGB4 and TLR4 and
HLA class II with ITGB1 orchestrate divergent intracellular signaling programs in allograft endothelium inducing
functions that promote monocyte recruitment to the graft and macrophage polarization. We propose infiltrating
monocytes encounter local EC-derived factors and IgG-FcγR signals that prime them for differentiation. In the
graft, the proangiogenic/profibrotic macrophages drive neointimal thickening. Antagonizing EC activation
and/or monocyte recruitment may represent viable therapeutic targets to arrest cAMR and protect grafts from
TV. We will employ a primary human EC culture model, a mouse cardiac allograft model of TV and human
cardiac explants with TV to dissect the HLA I and II signaling pathways and mechanisms of monocyte
recruitment and polarization. Aim 1: Define the structural requirements for complex formation and functional
crosstalk between HLA Class I and its co-receptors ITGB4 and TLR4 in mediating endothelial cell activation,
monocyte recruitment and macrophage polarization in cardiac TV. We will: (1a) determine how HLA I Ab-
activated EC poise infiltrating monocytes to polarize to macrophages with distinct phenotypes and functions in
vitro; (1b) characterize monocyte recruitment, TV lesion formation and phenotypes of infiltrating macrophages
during MHC I antibody-mediated allograft injury and development of TV; (1c) define the structural requirements
and functional effects of molecular crosstalk between ITGB4, TLR4 and HLA I on monocyte recruitment and
macrophage polarization by Ab-activated EC in vitro; and (1d) characterize the requirement for MHC I co-
receptors TLR4 and ITGB4 in monocyte recruitment, macrophage polarization and TV lesion formation in
murine cardiac transplants. Aim 2. Define the structural requirements for complex formation and functional
crosstalk between HLA class II and its co-receptor ITGB1 in mediating endothelial cell activation, monocyte
recruitment and macrophage polarization in cardiac TV. We will: (2a) determine how HLA II Ab-activated EC
poise infiltrating monocytes to polarize to macrophages with divergent phenotypes and functions in vitro; (2b)
characterize monocyte recruitment, vascular lesion formation and phenotypes of infiltrating macrophages in a
murine cardiac transplant model of MHC II cAMR and TV; (2c) define the structural requirements and
functional effects of molecular crosstalk between ITGB1 and HLA II on monocyte recruitment and macrophage
polarization by Ab-activated EC in vitro; (2d) characterize the requirement for MHC II coreceptor ITGB1 in
monocyte...

## Key facts

- **NIH application ID:** 9986649
- **Project number:** 5R01AI135201-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ELAINE F REED
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,649
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986649

## Citation

> US National Institutes of Health, RePORTER application 9986649, The role of HLA and its coreceptors in endothelial cell activation and leukocyte recruitment in antibody-mediated transplant rejection (5R01AI135201-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986649. Licensed CC0.

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