# Diversity of TFH cells and DSA generation after kidney transplantation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $657,643

## Abstract

ABSTRACT
One biomarker that has a strong association with poor long-term kidney allograft outcomes is the
presence of DSA. Recent advances in transplantation medicine have further established that DSA may
convey a wide range of injuries to the allograft, from acute ABMR to subclinical ABMR or to the absence
of injury. The early immunologic mechanisms that mediate these heterogeneous events are not well
understood. If such mechanisms were to be characterized, then IS therapy could be targeted and tailored
to provide the most benefit to high risk patients, without wide spread application of IS which can hurt
patients who do well. Our goal is to characterize the immunologic mechanisms (cellular and molecular)
that proceed and govern the development of DSA leading or not to ABMR, and to long-term poor
allograft outcomes. T follicular helper (TFH) cells are CD4+ T cells specialized in the cognate control of
antigen (Ag)-specific B cell immunity. They participate to the germinal centers (GC) formation in the
secondary lymphatic organs, where they provide critical help to naïve B lymphocytes to differentiate into
memory B cells, as well as to generate short-lived plasmablasts (PB) and long-lived plasma cells (PC)
that secrete high-affinity, isotype switched IgG responses. TFH cells also help memory B cells during
recall responses to differentiate into Ab-producing cells. While TFH cell subsets can distinctly shape the
functional quality of antibodies, they themselves can be (re)-programed by inflammatory or anti-
inflammatory signals into efficient or suboptimal helpers, underscoring their plasticity. Analysis of TFH
cells has proved valuable in humans, as they correlate well with Ab responses post-vaccination and with
disease activity in autoimmunity. Very little is known about the role TFH in organ transplantation and their
contribution to DSA generation. We have recently identified an association between elevation of Th1-TFH
cells and development of asymptomatic DSA in a cohort of Thymoglobulin-induced KTx recipients,
whereas activated Th1/Th17-TFH cells were detected in circulation of patients at ABMR diagnosis. Our
central hypothesis is that donor-reactive cTFH from patients before KTx are heterogeneous, and
depending on how lymphopenia induced proliferation (LIP) (re)programs them into efficient or suboptimal
helpers, they can distinctly shape DSA quality with clinical consequences for allograft survival. Therefore
in this grant we propose to investigate in Aim 1 the characteristics of allo-reactive memory TFH cells
phenotype, TCR clonality and function. In Aim 2 we will ascertain how post-Tx inflammation at the time of
T cell repopulation after T cell induction influences cTFH cells (re)-polarization. Aim 3 will assess whether
cTFH cells shape DSA quality, correlate with ABMR and early (1 year) and late (3-yr) allograft outcomes.

## Key facts

- **NIH application ID:** 10101606
- **Project number:** 5R01AI130010-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** DIANA M METES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $657,643
- **Award type:** 5
- **Project period:** 2017-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101606

## Citation

> US National Institutes of Health, RePORTER application 10101606, Diversity of TFH cells and DSA generation after kidney transplantation (5R01AI130010-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10101606. Licensed CC0.

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