# HVEM pathway regulating FRC function and transplant tolerance

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $511,721

## Abstract

Abstract
Lymph nodes (LNs) are the quintessential organs of immunity. Our understanding of how LNs control
alloimmune responses has evolved significantly with recent advances which highlight the function of specific
cellular and stromal components of the LN. Presentation of donor alloantigen to recipient T cells in the LN is
fundamental to the priming of allo-reactive T cells and subsequent allograft rejection. A recently recognized,
new dimension to this pervasive concept is that the LN is also critically important for transplant tolerance.
These multifaceted functions reflect the status of LNs as extremely specialized organs with unique
microvasculature, and a stromal compartment that is molded and regulated by resident mesenchymal cells
known as fibroblastic reticular cells (FRCs). The overall hypothesis of this project is that sustained activation
of FRCs in the draining LN (DLN) following transplantation results in their transformation to scar-forming pro-
inflammatory myofibroblasts, which further promote alloimmunity. Our studies will focus mechanistically on the
importance of the LIGHT/HVEM signaling pathway to the differentiation of FRCs into proinflammatory
myofibroblasts in the LN following transplantation. Our corollary hypothesis is that restoration of the native
function of FRCs through targeted drug delivery to LNs will enhance their immunoregulatory function and
promote tolerance. We are proposing three AIMS as follows: In AIM 1, we will examine the role of the
LIGHT/HVEM pathway in regulating the function of FRCs, controlling extracellular matrix (ECM) accumulation,
and mediating transplant immunity. Using global LIGHT and HVEM knockout mice, and mice with conditional
knockout of HVEM on FRCs, we will gain mechanistic insights into how the LIGHT/HVEM pathway controls the
differentiation of FRCs and transplantation outcomes. In AIM 2, we will study the importance of senescence in
determining the balance between the pro-inflammatory and anti-inflammatory properties of FRCs. We will use
a number of innovative conditional knockout mice to decipher the mechanisms by which senescent FRCs
promote alloimmunity following transplantation. In AIM 3, we will determine whether delivering healthy FRCs
and senolytic agents to the DLN will restore its microarchitecture and regulate alloimmunity following
transplantation. The data from these studies will lay the groundwork for the first time to develop innovative
therapeutic strategies aimed at manipulating the microenvironment within LNs. This provides a unique
opportunity to direct the alloimmune response following transplantation towards tolerance. This proposal
establishes a multidisciplinary collaborative team to produce novel mechanistic data, which will provide the
basis for highly innovative and selective therapeutic strategies for transplantation. Therefore, this proposal can
make transformative advances in the field of organ transplantation.

## Key facts

- **NIH application ID:** 10024596
- **Project number:** 1P01AI153003-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $511,721
- **Award type:** 1
- **Project period:** 2020-07-27 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024596

## Citation

> US National Institutes of Health, RePORTER application 10024596, HVEM pathway regulating FRC function and transplant tolerance (1P01AI153003-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10024596. Licensed CC0.

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