# Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection

> **NIH NIH R03** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $134,250

## Abstract

Project Summary
Cancer immunotherapy has become a standard therapy for many cancers. However, it’s associated with acute
kidney injury, resulting in significantly increased mortality. Acute interstitial nephritis is the most common acute
kidney injury, affecting 2-3% of the patients receiving immune checkpoint inhibitors (ICIs). In addition, 40% of
the kidney transplant patients receiving ICIs suffer from acute rejection, and once rejection occurs, 65% lose
allograft and require renal replacement therapy. Thus, understanding the mechanisms of ICI-associated acute
kidney injury and finding therapies is critical. My K08 project aims to understand the roles of immune
checkpoint molecules (PD-1 and CTLA-4) in kidney inflammation, by using the novel animal models that
express neoantigen peptides specifically in kidney proximal tubules and tracking antigen-specific T cell
response in the animals by tetramer staining technique. The results showed that the presence of antigen-
specific T cells and ICIs trigger the immune cell infiltration to the kidneys, mimicking acute interstitial nephritis
seen in the cancer patients treated with ICIs. While animal models are ideal to address the precise molecular
mechanisms of the disease, there’s a limitation in the applicability of the findings to the human disease. The
largest multicenter clinical study that I led recently found that the ICI-associated kidney injury occurs much
faster and more robust in kidney transplant recipients compared to non-kidney transplant patients. The findings
led to my central hypothesis that pre-existing donor antigen-specific T cells in the kidney transplant recipients
are quickly activated, proliferated in the presence of ICIs, and cause direct kidney injury. In this pilot study, I
propose to perform high dimensional analyses using human tissue samples to track antigen-specific T cells by
single cell RNA sequencing and T cell receptor (TCR) repertoire analysis. We will analyze the TCR clonotype
and phenotype of antigen-specific T cells, using the archived peripheral blood mononuclear cells, tumor and
kidney biopsy samples, obtained from the patients who had acute graft rejection after cancer ICI therapy, by
collaborating with Center of Immuno-Oncology at Dana Faber Cancer Institute and single cell genomics core at
Brigham and Women’s Hospital. This pilot project tests the feasibility of the high dimensional analysis of the
patient samples for a future prospective clinical trial in the patients with ICI-associated kidney injury. If feasible,
we will incorporate these analyses in the prospective clinical trial, which will eventually help understand the
mechanism of acute interstitial nephritis and acute graft rejection in the patients treated with cancer
immunotherapy.

## Key facts

- **NIH application ID:** 10351987
- **Project number:** 1R03DK131223-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Naoka Murakami
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $134,250
- **Award type:** 1
- **Project period:** 2022-01-07 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351987

## Citation

> US National Institutes of Health, RePORTER application 10351987, Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection (1R03DK131223-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10351987. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*