# Contribution of CMV-specific T cells to chronic kidney rejection

> **NIH NIH K01** · STANFORD UNIVERSITY · 2020 · $154,083

## Abstract

Project Summary
Kidney transplantation is life-saving for people with end stage kidney disease (ESKD). However, complications
including opportunistic infection and chronic T cell- and antibody-mediated rejection reduce long-term graft
survival. Seropositivity for cytomegalovirus (CMV) is associated with higher rates of chronic rejection after
transplantation. Chronic exposure to CMV induces immunosenescence in CMV-responsive memory T cells,
including loss of proliferative capacity and differentiation potential, with maintained production of inflammatory
cytokines. In consequence, these cells become less protective, and may even promote rejection. My
preliminary data suggest that the development of senescence in response to CMV is accelerated after
transplantation. In addition, T cell mediated infiltration of inflammatory macrophages into kidney grafts can
induce rejection. Macrophages are a major site of CMV infection. Together, these observations led to the
hypothesis that senescent CMV-responsive T cells contribute to chronic rejection that will be tested
through two aims. The goal of the first aim is to characterize senescence in CMV-responsive T cells post-
transplant. CMV-responsive T cells will be analyzed at post-transplant time points before and after the onset of
acceleration of senescence. Characterization will include in-depth gene expression profiling by single cell RNA
sequencing and functional assays for chromatin accessibility, telomere length, and proliferation. The goal of
the second aim is to determine whether CMV-responsive T cells and inflammatory macrophages influence
susceptibility to chronic rejection. Quantity and localization of infiltration of both CMV-specific T cells and
macrophages into kidney allografts will be measured in archived biopsy specimens, comparing patients
diagnosed with chronic rejection to a control group of patients with chronicity. Phenotypic analysis of blood T
cells at the time of transplant biopsy will identify populations correlated with rejection, which in the long-term
may provide a new diagnostic of rejection. The career plan is for the PI to become an independent investigator
researching the effects of immune complications on kidney transplant. The research environment at Stanford is
well suited for these studies, given access to core facilities for sequencing, flow cytometry, and microscopy.
The aims provide opportunities to gain expertise in collaboration with bioinformaticians, statisticians,
nephrologists, and pathologists, which are key to the career plan. Specifically, Aim 1 involves collaboration with
Dr. Purvesh Khatri for complex data analysis of sequencing data sets. Aim 2 involves collaboration with
transplant nephrologists Drs Jane Tan and Paul Grimm and pathologist Dr. Neeraja Kambham for analysis and
interpretation of biopsy results. It also involves collaboration with renal cell carcinoma researcher Dr. Wendy
Fantl and statistician Dr. Robert Tibshirani for highly multiplexed an...

## Key facts

- **NIH application ID:** 10054619
- **Project number:** 1K01DK123196-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lauren Higdon
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $154,083
- **Award type:** 1
- **Project period:** 2020-07-08 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054619

## Citation

> US National Institutes of Health, RePORTER application 10054619, Contribution of CMV-specific T cells to chronic kidney rejection (1K01DK123196-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10054619. Licensed CC0.

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