# High-throughput identification and transcriptional analysis of autoreactive T cells in individuals with membranous nephropathy.

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $209,500

## Abstract

SUMMARY
 Membranous nephropathy (MN) is a glomerular disease due to the deposition of anti-podocyte antibodies
in the subepithelial space of the glomerular basement membrane. This leadis to complement-mediated podocyte
injury and, in ~30% of patients, to the development of end stage kidney disease within 10 years from diagnosis.
Most of the research in MN has focused on the autoantibody specificities and has led to the identification of
phospholipase 2A receptor (PLA2R) as the main target antigen in 70%-80% of the patients. Conversely, little is
known on autoreactive T cells, despite the evidence from other antibody-mediated autoimmune diseases clearly
showing a critical pathogenic role of autoreactive T cells, efficacy of T cell targeting treatments, and our
preliminary data documenting that autoreactive T cells are present in the circulation of MN patients.
 Aim 1 of the present project will develop a new strategy to capture the T cell receptor (TCR) repertoire of
PLA2R-reactive T cells in MN patients. We will apply high-throughput paired T cell receptor alpha and beta chain
DNA sequence capture for renewable TCR gene library generation and functional screening from patient T cells.
We will physically link TCR gene sequences for cloning into cellular display libraries, enabling repeated in vitro
functional analyses of TCRs in ways that are impossible with alternative available techniques. Aim 2 will apply
these technologies for the study of the single-cell transcriptional profile of CD4+ T cells. These data will reveal
the characteristics of autoreactive TCRs in a previously collected samples from MN patients with remission
versus active disease, setting the stage for expanded clinical studies.
 Overall, this project will collect and analyze immune response data from MN patients with unprecedented
molecular scope and scale. Our approach is innovative because it couples carefully designed clinical sample
sets with new high-throughput approaches in TCR analysis to comprehensively interrogate the molecular
mechanisms of T cell responses in MN patients. The proposed research is significant because it will provide
important tools for mechanistic studies aimed at identifying new biomarkers and therapeutic targets for MN
patients.

## Key facts

- **NIH application ID:** 10908643
- **Project number:** 5R21AI178021-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Paolo Cravedi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,500
- **Award type:** 5
- **Project period:** 2023-08-16 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908643

## Citation

> US National Institutes of Health, RePORTER application 10908643, High-throughput identification and transcriptional analysis of autoreactive T cells in individuals with membranous nephropathy. (5R21AI178021-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908643. Licensed CC0.

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