# In Vivo Prevention of Murine GVHD

> **NIH NIH R37** · UNIVERSITY OF MINNESOTA · 2020 · $486,950

## Abstract

Our focus for years in graft-vs-host disease (GVHD) has been on stopping Teffector (Teff) activation
and expansion. We now believe that successful GVHD prevention can never be achieved unless we
coordinate and control the fundamental process of gut tissue repair. Tissue repair can be inherently
inflammatory. We will test the hypothesis that anti-inflammatory innate lymphoid type 2 cells (ILC2) are capable
of tissue repair without inflammation. Aim 1 will focus on a novel exogenous peri-bone marrow transplant
(BMT) (d-10 to +4) IL33 approach initiated prior to total body radiation (TBI)-induced inflammation that primes
the environment to support ILC2s (aim 1A). We show that that preconditioning IL33 increases host ILC2s by
>100-fold even in TBI treated mice. We test the hypothesis that pre-TBI IL33 given along with early post-BMT
IL33 will support infused donor ILC2s (aim 1A). Since ILC2s express arginase-1 and amphiregulin (AREG), we
will test the hypothesis that arginase-1 and AREG may cooperate to repair tissues while minimizing immune
mediated inflammation (aim 1B). Because 50% of gut regulatory T cells (Tregs) are IL33R+ that can survive
TBI, we will test the hypothesis that host Tregs work in concert with ILC2s to contribute to the tissue reparative
and anti-GVHD effects of IL33 and infused donor ILC2s (aim 1B). To examine the direct gut reparative effects
of IL33 and its immunoregulatory (ILC2s; Tregs) targets, small intestinal organoid cultures will be utilized to test
the direct effects of cytokines/proteins that support (IL25) or are produced (IL13; AREG) by ILC2s and Tregs
(aim 1B). In clinical studies, circulating donor ILC2 recovery was slow after allo-transplant and ILC recovery
affected GVHD development. We show that host gut (lamina propria, LP) ILC2 in conditioned mice are
markedly reduced and ILC2 fail to repopulate the LP for ≥84 days in allo-BMT recipients. Aim 2 will determine
rate-limiting factors impeding rapid recovery of ILC2s and develop strategies to overcome this deficiency. We
will test the hypothesis that donor ILC2 precursors receive inadequate signals due to TBI mediated tuft cell
injury creating an IL25 deficiency state. Without IL25, we hypothesize that immature donor ILC2 differentiation
and maturation, and infused donor ILC2 longevity is compromised. We will test the hypothesis that
endogenous IL25 deficiency can be circumvented by exogenous IL25 administration and that donor ILC2
derived IL13 will promote tuft cell regeneration and IL25 production, reversing the IL25 deficiency state (aim
2A). In aim 2B, we will test the hypothesis that ILC2 generation from ILC2 precursors is not supported due to
the presence of pro-inflammatory signals (IFNg, IL12/23; retinoic acid) up-regulated during GVHD, which then
results in the loss of donor and host ILC2 anti-inflammatory effects (aim 2B). Using uniquely available mice,
reagents and small intestinal organoid cultures, our expert team will collaborate to develop new ther...

## Key facts

- **NIH application ID:** 9955197
- **Project number:** 5R37AI034495-28
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bruce R Blazar
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,950
- **Award type:** 5
- **Project period:** 1993-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955197

## Citation

> US National Institutes of Health, RePORTER application 9955197, In Vivo Prevention of Murine GVHD (5R37AI034495-28). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9955197. Licensed CC0.

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