# Mechanisms of Selective CD28 Blockade on T Follicular Helper Cell-mediated Donor-specific Antibody Responses in Transplantation

> **NIH NIH K08** · EMORY UNIVERSITY · 2020 · $188,676

## Abstract

Project Summary/Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although short-term
outcomes are excellent, long-term allograft survival rates remain inadequate. It has been increasingly
recognized that anti-HLA donor-specific antibodies (DSA) play a significant role in the development of chronic
rejection and fibrosis that lead to late renal allograft loss. The mechanisms that underlie the generation of DSA
are poorly understood; therefore, a better understanding of the cellular mechanisms responsible for DSA
formation following transplantation has potential to guide the optimization of current immunosuppressive
strategies and the development of novel therapies to control DSA. The applicant for this K08 career
development award is an early career abdominal organ transplant surgeon with a strong background in
preclinical nonhuman primate models and clinical transplantation seeking to enhance his knowledge of basic
immunology and acquire advanced skills in experimental mouse models to answer the fundamental
mechanistic questions necessary to realize bench-to-bedside translation of novel approaches to control DSA in
kidney transplant recipients. In this application, he proposes to examine the costimulatory and coinhibitory
mechanisms that drive T follicular helper (Tfh) cell-mediated DSA responses in the setting of CD28
costimulation blockade in a murine skin transplant model. Through a series of interrelated experiments, he will
test the hypothesis that improved inhibition of Tfh cell and DSA responses following transplantation with
selective CD28 blockade is dependent upon the coinhibitor CTLA-4, and that CTLA-4 is mediating its
coinhibitory effect on DSA in a Tfh-intrinsic manner. The work will also examine if reduced expression of the
costimulator ICOS on Tfh cells is a mechanism of anti-CD28-induced DSA inhibition. The overall goal of this
project is to elucidate the mechanistic underpinnings of costimulation blockade-mediated Tfh cell inhibition and
DSA prevention. The proposed work is aligned with the NIAID strategic priority of identifying therapeutic targets
for the enhancement of translational efforts to extend renal allograft survival through preclinical research. A
first-class mentor team, led by primary mentor Mandy Ford, PhD, and co-mentors Christian Larsen, MD, DPhil
and Larry Boise, PhD, will support the applicant's immediate goal of launching his independent research
career. In the process, through formal coursework and a structured professional development plan, this K08
will help the applicant build a platform from which to pursue his long-term career goal of creating a translational
research program that links findings on the basic mechanisms of Tfh cell-mediated DSA formation to clinical
observations in transplant recipients to advance the ability to control anti-HLA antibodies in kidney
transplantation.
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## Key facts

- **NIH application ID:** 9928886
- **Project number:** 5K08AI132747-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Idelberto Raul Badell
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,676
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928886

## Citation

> US National Institutes of Health, RePORTER application 9928886, Mechanisms of Selective CD28 Blockade on T Follicular Helper Cell-mediated Donor-specific Antibody Responses in Transplantation (5K08AI132747-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928886. Licensed CC0.

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