# Targeting IL-18 in Thymic Regeneration

> **NIH NIH F30** · UNIVERSITY OF WASHINGTON · 2024 · $53,974

## Abstract

ABSTRACT
Targeting IL-18 in Thymic Regeneration
 The thymus, the organ responsible for T cell development, is both highly sensitive to acute injury and
capable of regeneration. However, the thymus progressively loses its function with age such that there is
markedly reduced capacity for T cell production and recovery from damage even early in adulthood. The
thymus is particularly sensitive to pre-hematopoietic stem cell transplant (HCT) cytoreductive conditioning.
Therefore, transplant recipients are at increased risk of opportunistic infection as well as relapse of malignancy
during a prolonged period of T cell deficiency. No clinically approved strategies currently exist to improve
thymic function and treat lymphopenia. Better understanding endogenous pathways of thymic damage and
regeneration may inform therapeutic strategies to this end.
 Here, we provide evidence supporting the involvement of pyroptosis induced interleukin-18 (IL-18) as a
negative regulator of thymopoieisis following acute injury and propose its targeting for improving organ function
in settings of lymphopenia. Aim 1 of this study investigates the source of this suppressive IL-18 following acute
damage by sublethal irradiation (SL-TBI) and its downstream cellular effectors. Specifically, we investigate
thymic epithelial cells (TECs) and innate lymphoid cells within the thymus as effectors of IL-18’s mechanism of
action. Aim 2 of this study proposes the temporal attenuation of IL-18 signaling using anti IL-18 monoclonal
antibody as a novel therapeutic strategy to improve thymic recovery, and subsequently, peripheral T cell
reconstitution and function. I put forward clinically relevant transplant models to assess its potential for
improving regeneration post-HCT. Additionally, I will assess the potential of blocking IL-18 signaling in aged
models of thymic involution. Together, these studies will not only provide insight into the biological mechanisms
of tissue injury and repair, but also will offer an innovative therapeutic strategy to boost immune function
especially in recipients of HCT.

## Key facts

- **NIH application ID:** 10894624
- **Project number:** 5F30HL165761-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** David William Granadier
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-06-16 → 2025-06-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894624

## Citation

> US National Institutes of Health, RePORTER application 10894624, Targeting IL-18 in Thymic Regeneration (5F30HL165761-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10894624. Licensed CC0.

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