# Harnessing endogenous mechanisms of thymic regeneration toboost immune function in recipients of hematopoietic cell transplant

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $568,505

## Abstract

PROJECT SUMMARY
 Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock,
or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable
capacity for endogenous repair. Although there is continual thymic involution and regeneration in response to
everyday insults like stress and infection, acute and profound thymic damage caused by common cancer
therapies and the conditioning regimes used as part of hematopoietic cell transplantation (HCT), leads to
prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may
even facilitate cancer relapse. Furthermore, this capacity for regeneration declines further as a function of age.
 We have previously identified two independent pathways of endogenous thymic regeneration, centered
on the production of the regeneration-associated factors (RAFs) IL-22 by innate lymphoid cells (ILCs), and
BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial
cells. Although we and others have previously identified dendritic cell (DC)-produced IL-23 as critical for
controlling the production of IL-22 by ILCs, the underlying mechanisms that trigger the regenerative response
via the production of these distinct RAFs is poorly understood. In our preliminary data we have demonstrated
that deletion of the pattern recognition receptor NOD2 results in a significant increase in the production of IL-
22, IL-23, and BMP4, leading to improved thymus recovery after damage caused by total body irradiation. This
suggests that under steady-state conditions, NOD2 signaling suppresses the production of these regenerative
cytokines; but after damage this negative stimulus is removed, thereby enabling tissue repair by activating the
production of RAFs. Based on these findings, we hypothesize that (a) intrinsic NOD2 signaling in DCs and
ECs suppresses the production of IL-23 and BMP4, respectively; (b) NOD2-mediated suppression of
RAFs is abolished after damage by the depletion of thymocytes; and (c) that this common pathway of
regeneration can be exploited into a superior method to promote thymic function following HCT.
 Specifically, our proposal has the following aims: (1) To investigate the role of NOD2 in regulating
endogenous thymic regeneration after acute damage; (2) To identify the regulators of NOD2 signaling that
suppress the steady-state production of RAFs; and (3) To study if these pathways can be modulated as a
means of improving T cell reconstitution following HCT.
 The mechanistic and pre-clinical studies outlined in this proposal not only have the potential to define
important novel pathways underlying tissue regeneration, but could also result in innovative clinical approaches
to enhance T cell reconstitution in recipients of HCT, as well as patients whose thymus has been decimated
due to age, infection or other cytoreductive cancer ther...

## Key facts

- **NIH application ID:** 9840507
- **Project number:** 5R01HL145276-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Jarrod Dudakov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $568,505
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840507

## Citation

> US National Institutes of Health, RePORTER application 9840507, Harnessing endogenous mechanisms of thymic regeneration toboost immune function in recipients of hematopoietic cell transplant (5R01HL145276-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840507. Licensed CC0.

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