# Mechanisms of Immune Activation in Hypertension

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $751,897

## Abstract

PROJECT SUMMARY
In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of
hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in
hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen
presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that
are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are
increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells,
particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of
isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and
by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are
defining potential immunogenic peptides presented in MHC class 1 and determining if there are different
peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be
employed to determine if similar isoLG modified peptides are presented by monocytes of humans with
hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the
Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T
cell receptors (TCRα and TCRβ) in activated T cells of both mice and humans using single cell sequencing.
This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their
responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We
have recently shown that hypertensive humans have a striking increase in circulating memory T cells that
produce IL-17A and IFN-γ compared to matched controls. Data from single cell sequencing will identify the
TCRα and TCRβ of these cells and to produce transfectomas expressing these sequences and to determine if
they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual.
Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this
disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in
hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension.
Specific therapies to reduce isoLG formation have proven effective in experimental models and have
substantial promise for treatment of human hypertension.

## Key facts

- **NIH application ID:** 10075957
- **Project number:** 5R35HL140016-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David G Harrison
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $751,897
- **Award type:** 5
- **Project period:** 2018-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075957

## Citation

> US National Institutes of Health, RePORTER application 10075957, Mechanisms of Immune Activation in Hypertension (5R35HL140016-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10075957. Licensed CC0.

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