# Lymph node stromal senescence and transplant immunity

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $588,282

## Abstract

Abstract
The steadily increasing elderly population and its rising incidence of organ failure have led to a burgeoning
number of aged patients on the waitlist for solid organ transplants. Lymph nodes (LNs) play a critical role in
controlling alloimmune responses and formation of immune tolerance to transplantation under costimulatory
blockade. LN stromal cells are referred to as fibroblastic reticular cells (FRCs). FRC are the chief architect of LN
by producing and maintaining the extracellular matrix (ECM) fibers upon which T cells that have entered through
high endothelial cells crawl to encounter dendritic cells (DCs), which present allo-antigens. In addition to
providing the LN scaffold, they also produce various chemokines that regulate the homing of T and B cells. The
trafficking of T cells to the LN and proper positioning of DCs are critical requirements for the generation of iTregs
following anti-CD40L treatment and suppression of alloreactive T cells. The role of aged FRCs in changing the
stromal microenvironment in aging LNs is a novel concept central to the pathogenesis of alloimmunity in elderly
transplant recipients, which remains to be fully explored. Pursuing our preliminary data, our main hypothesis is
that aging-associated senescence of FRCs transforms them to pro-inflammatory myofibroblasts that create an
immunostimulatory LN microenvironment that produces resistance against the promotion of graft acceptance
under costimulatory blockade. Aged LNs contain a significant accumulation of ECM, and aged FRCs experience
a high level of senescence, resulting in an increase in the population of pro-inflammatory T cells. FRCs are
derived from lymphoid tissue organizer cells in a lymphotoxin β-receptor (LTβR)-dependent manner. We further
hypothesize that LTβR signaling in aged FRCs plays a critical role in regulating their immunoregulatory function
and the fate of transplant tolerance. Pursuant to our preliminary data, we will test the hypothesis that FRC
therapy and/or targeted delivery of an LTβR agonist will rejuvenate the LN stroma of aged mice, supporting the
tolerogenic effect of ant-CD40L. We are proposing three AIMS as follows. AIM 1 will study the mechanisms by
which aging-associated senescence in FRCs regulates alloimmunity in the LN. AIM 2 will examine the
importance of lymphotoxin pathways in aged LN stroma and transplant immunity. AIM 3 will study novel
approaches to rejuvenate aged LN stroma to restore immune tolerance following anti-CD40L treatment.

## Key facts

- **NIH application ID:** 10862424
- **Project number:** 1P01AI175397-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,282
- **Award type:** 1
- **Project period:** 2024-05-03 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862424

## Citation

> US National Institutes of Health, RePORTER application 10862424, Lymph node stromal senescence and transplant immunity (1P01AI175397-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10862424. Licensed CC0.

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