# Regulation of graft versus host disease with in vivo generated regulatory T cells

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Bone marrow transplantation (BMT) is a curative approach for treating hematological
malignancies and other life-threatening disorders. Military servicemen are under risk to develop
such lethal conditions as a result of exposure to carcinogens – like agent orange – during their
active service. The success of BMT is limited by graft versus host disease (GVHD), a lethal
inflammatory complication of BMT. GVHD is driven by donor leukocyte subsets, such as donor
T lymphocytes that are important for both bone marrow engraftment and the prevention of tumor
recurrence. Novel treatment strategies are needed to keep donor T lymphocytes in the graft in
order to maintain donor T lymphocyte-mediated anti-tumor (graft versus tumor; GVT) immunity
while suppressing the GVHD. One novel approach to this is therapeutic stimulation of the
function of regulatory T cells (Tregs). Our experiments show that augmentation of intestinal
immune regulation induces Tregs in vivo, resulting in the suppression of GVHD and the
preservation of anti-tumor immunity. We induce intestinal immune regulation, or “conditioning,”
using a completely novel approach: self-limited colonization of the gut with helminths, to
stimulate T helper 2 (Th2) immune pathways. In this application, we propose to test the central
hypothesis that the Th2 pathways are critical in intestinal immune conditioning, and that they
lead to the generation of Tregs in vivo. We will use the murine nematode, Heligmosomoides
polygyrus bakeri (Hpb) to infect mice. We will induce acute GVHD in uninfected and helminth-
infected BMT recipients of MHC I/II major mismatch donors. To assess the roles of Th2 and
Th2-associated pathways in regulating GVHD and the in vivo induction of Tregs, we will employ
complementary genetic and pharmacological approaches. We will determine the mechanisms
through which intestinal immune conditioning increases the regulatory activity of Tregs, and
establish the extent to which helminth infection affects GVT immunity in mouse tumor models.
Furthermore, we will deliver immune regulatory and Th2-associated cytokine, interleukin 10
microparticles into the gut of uninfected mice by oral gavage, to mimic helminth-induced
intestinal immune conditioning. The findings from these studies are expected to help us achieve
our long-term goals, which are to: identify the cellular and molecular immune regulatory
pathways that are key to helminthic immune conditioning in preclinical models; and to apply this
knowledge to veterans and other patient populations that undergo BMT. No significant side
effects have been associated with helminth infection in immune suppressed patient groups, like
individuals with inflammatory bowel disease or multiple sclerosis. Thus, the targeting of
helminth-modulated signaling pathways – using small molecules, helminth products or possibly
even intact helminths – may be a safe and potent treatment for GVHD that leaves the beneficial
GVT immunity intact.

## Key facts

- **NIH application ID:** 9863988
- **Project number:** 5I01BX002906-04
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Mirac Nedim Ince
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9863988

## Citation

> US National Institutes of Health, RePORTER application 9863988, Regulation of graft versus host disease with in vivo generated regulatory T cells (5I01BX002906-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9863988. Licensed CC0.

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