# Lymph nodes at the crossroads of allo immunity and regulation

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $1,269,545

## Abstract

OVERALL – SUMMARY/ABSTRACT
Organ transplantation remains a mainstay therapeutic strategy for patients with end organ diseases. One of
the highest unmet needs to improve long-term transplant outcomes is devising more effective immune
modulation. This requires innovative mechanistic studies of transplant alloimmunity. The lymph node (LN) is
the quintessential organ of alloimmunity. While the recognition of alloantigens in the LN is fundamental to the
generation of alloreactive T cells, our groups also have shown that the LN plays an important role in
alloimmune-regulation and Treg-mediated tolerance. These multifaceted functions rest on the nature of LNs as
extremely specialized organs with unique microvasculature, stromal fibers, and stromal cells (referred to as
fibroblastic reticular cells [FRCs]). Our overarching hypothesis is that manipulating the microenvironment of
LNs will provide a unique opportunity to direct the alloimmune reaction towards an anti-inflammatory tolerance
response. Our major goals are to understand the cellular and molecular mechanisms that govern the
microanatomical adaptation of the LN during immune activation or tolerance induction, and to develop highly
innovative therapeutic strategies that promote a regulatory LN microenvironment and result in immune
tolerance. This PPG sets forth a platform for connecting two teams (Drs. Abdi and Bromberg) with
complementary skills and expertise in LN alloimmune-biology. Project 1 will test the hypothesis that
sustained activation of FRCs of the LN during alloimmunity will result in FRC transformation to proinflammatory
myofibroblasts creating an inflammatory milieu within the LN, which would further promote alloimmunity. Our
corollary hypothesis is that restoration of the function of FRCs and microanatomy of the LNs will enhance
their immunoregulatory function and promote tolerance. Aim 1 will examine the role of the HVEM/LIGHT
pathway in the differentiation of FRCs into proinflammatory myofibroblasts, thereby creating an inflammatory
milieu within the LN microenvironment and promoting transplant immunity. Aim 2 will investigate the
mechanisms by which fibrotic FRCs promote a pro-inflammatory response in the LN. Aim 3 will reprogram the
stroma of LNs via FRC delivery or LN-targeted delivery of senescence inhibitors to further promote alloimmune
tolerance. Project 2 will test the hypothesis that FRCs regulate the LN laminin α4:α5 (LAMA4/LAMA5) ratio
and control the fate of the immune response. Aim 1 will define the role of stromal cells in controlling the
balance of LAMA4 and LAMA5. Aim 2 will define the role of LTβR as a key pathway in regulating the formation
of LAMA5. Aim 3 will use targeted delivery of anti-CD40L and anti-LAMA5 mAbs to the LN to promote
tolerance. An Administrative Core (Core A) and Nanoparticle and FRC Core (Core B) will provide the
infrastructure and resources to support these two projects. The ultimate goal of these well-integrated and
highly synergistic Proj...

## Key facts

- **NIH application ID:** 10431918
- **Project number:** 5P01AI153003-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,269,545
- **Award type:** 5
- **Project period:** 2020-07-27 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431918

## Citation

> US National Institutes of Health, RePORTER application 10431918, Lymph nodes at the crossroads of allo immunity and regulation (5P01AI153003-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10431918. Licensed CC0.

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