# Role of Autoreactivity in pathogenesis of chronic graft versus host disease

> **NIH NIH R56** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $342,596

## Abstract

Chronic graft versus host disease (cGVHD), a systemic autoimmune syndrome, remains the major cause of
morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). During
the past funding period, we used murine and humanized murine models of cGVHD and biospecimens from
cGVHD patients to demonstrate that CD4+ T cells and B cells and their interactions in non-lymphoid tissues
affected by cGVHD such as the liver, lung and skin play a critical role in the pathogenesis and persistence of
the disease. The premise of this renewal proposal is that deeper mechanistic understanding of the
interactions between non-circulating tissue-resident CD4+ memory T (Trm) and tissue-resident B (Brm)
cells in GVHD target tissues will identify new therapeutic targets for prevention or treatment of cGVHD.
In Aim 1, we will determine how murine and human Trm subsets such as PSGL1hi and PSGL1loCD4+ Trm cells
mediate pathogenesis in target tissues. We will dissect how TCR-signaling triggered by donor- or recipient-type
antigen-presenting cells and down-stream signaling and nuclear transcription factors such as STAT3,
HOBIT/Blimp-1 and the tissue environmental alarmin IL-33 regulate Trm differentiation, expansion and
function. Finally, we will attempt to develop a novel technology to target STAT3 in donor T cells, because we
have observed that STAT3 deficiency in donor T cells effectively prevents cGVHD, with a marked reduction in
the numbers and function of Trm cells in GVHD target tissues. In Aim 2, we will test whether murine and
human Brm cells produce antigen-specific IgG to augment fibrosis in cGVHD target tissues. We will test
whether Brm differentiation requires help from PSGL1loCD4+ T cells. We anticipate that targeting STAT3 in
donor T cells will simultaneously prevent formation of pathogenic Trm and Brm cells. These studies are of high
biological and translational significance and may lead to a paradigm shift in our understating of cGVHD
pathogenesis and development of novel approaches for preventing and treating cGVHD.

## Key facts

- **NIH application ID:** 10393945
- **Project number:** 2R56AI066008-16
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Defu Zeng
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $342,596
- **Award type:** 2
- **Project period:** 2005-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393945

## Citation

> US National Institutes of Health, RePORTER application 10393945, Role of Autoreactivity in pathogenesis of chronic graft versus host disease (2R56AI066008-16). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393945. Licensed CC0.

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