# Vascular macrophages and T cells in atherosclerosis

> **NIH NIH R35** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2021 · $907,152

## Abstract

Abstract
This application proposes research designed to provide solid mechanistic underpinnings for immunotherapy
and vaccination to prevent and treat atherosclerosis. Vaccination with MHC-II restricted peptide epitopes from
apolipoprotein B (ApoB) ameliorates atherosclerosis by inducing ApoB-specific regulatory CD4 T cells (Tregs).
I have developed reagents (tetramers and dextramers) to detect and isolate these ApoB-specific Tregs at the
single cell level in mice and humans. The proposed work has a T cell aspect, currently supported by R01
HL121697 (2014-2018), and a vascular macrophage aspect, currently supported by R01 HL115232 (2012-
2022). To gain better mechanistic insight, I propose to adoptively transfer ApoB-specific Tregs (if necessary
expanded in Rag2-/- mice) into recipient mice and measure atherosclerosis. I will also transfer ApoB peptide-
specific antibodies to formally test possible antibody effects, and test the role of B cells in two B cell-deficient
mouse lines. I will study changes in functions of vascular macrophages in vivo after vaccination. To improve
the vaccine efficacy, I propose to test vaccine formulations similar to what would be used clinically, test the
atherosclerosis vaccines in two other mouse models of atherosclerosis (Apoe-/- on chow diet, Ldlr-/- on high fat
diet), optimize the vaccination protocol, and add low-dose IL-2 to stabilize Tregs. To discover how and why
Tregs switch to effector T cells, I will use FoxP3 (the Treg defining transcription factor) lineage tracker mice.
TCR-Seq will test the hypothesis that the apparent switch is caused by an outgrowth of a minor population of
pro-inflammatory ApoB-specifc CD4 T cells. To test cell-exogenous factors, I will incubate ApoB-specific CD4
T cells with explanted normal or atherosclerotic aortas, and measure epigenetic changes by DNA and histone
methylation around the FoxP3 locus. To prepare for translating the vaccine into humans, I propose more
human work, including mass cytometry (CyTOF) on peripheral blood mononuclear cells (PBMCs) with 42-
“color” panels. Barcoded scRNA-Seq to obtain single cell transcriptomes will define the cell types more deeply.
I propose to expand the current clinical data set (all women, most HIV+) to both genders and HIV-. When this
work is completed, we will have a good understanding how atherosclerosis vaccination works. We will have
extensive human data for the phenotype of ApoB-specific CD4 T cells in PBMCs collected from cardiovascular
disease cases and controls.

## Key facts

- **NIH application ID:** 10112954
- **Project number:** 5R35HL145241-03
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Klaus F. Ley
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $907,152
- **Award type:** 5
- **Project period:** 2019-03-18 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112954

## Citation

> US National Institutes of Health, RePORTER application 10112954, Vascular macrophages and T cells in atherosclerosis (5R35HL145241-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10112954. Licensed CC0.

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