# Notch Signaling in Alloimmunity

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $388,900

## Abstract

ABSTRACT Notch signaling in alloimmunity
Allogeneic T cell responses against foreign host antigens mediate graft-versus-host disease, the most
serious complication of allogeneic bone marrow transplantation (allo-BMT). During the first five years
of this proposal, we defined a new critical role of Notch signaling in alloreactive T cells mediating
graft-versus-host disease after allo-BMT. Inhibition of canonical Notch signaling in donor T cells
markedly reduced the severity and mortality of graft-versus-host disease in multiple mouse models of
allo-BMT. Notch blockade induced a unique pattern of immunomodulation in T cells, with decreased
production of inflammatory cytokines and increased expansion or regulatory T cells. However, in vivo
T cell proliferation, expansion in lympho-hematopoietic organs and cytotoxicity were preserved upon
Notch inhibition. Notch1/2 receptors in T cells and Delta-like1/4 (Dll1/4) Notch ligands in the host
played a dominant role. Dll1/4 inhibition emerged as a promising strategy to inhibit Notch signaling
without inducing side effects from systemic pan-Notch inhibition. Interestingly, we discovered that
short-term Dll1/4 inhibition in the peri-transplant period was sufficient to confer long-term protection
from morbidity and mortality. Dll1/4 blockade during the first 48 hours after allo-HCT was essential to
efficiently control graft-versus-host disease, suggesting that a critical early pulse of Notch signaling is
delivered to incoming donor T cells, with a long-lasting impact on their pathogenic functions.
Furthermore, we identified specialized radioresistant stromal cells in secondary lymphoid organs as
the critical source of Dll1/4 Notch ligands after lethal irradiation and allo-BMT. We hypothesize that
alloantigen-specific T cells form early contacts with resident subsets of non-hematopoietic stromal
cells in secondary lymphoid organs that drive T cell pathogenicity in graft-versus-host disease
through Dll1/4-mediated Notch signals. To explore this hypothesis in detail, we will investigate the
distribution of Dll1/4-expressing cells and test the importance of defined cellular sources of Notch
ligands in multiple models of graft-versus-host disease driven by major or minor alloantigen
mismatches, and with graded doses of irradiation; visualize and define the interaction of alloantigen-
specific T cells with cellular sources of alloantigens and Notch ligands in secondary lymphoid organs;
and explore the cellular and molecular mechanisms of Notch action in alloreactive T cells during their
initial window of Notch sensitivity in vivo. These studies will bring novel insights into the molecular
regulation of alloimmunity and might lead to the development of new approaches to limit damaging
consequences of T cell reactivity after allogeneic transplantation.

## Key facts

- **NIH application ID:** 9927981
- **Project number:** 5R01AI091627-11
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ivan Maillard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,900
- **Award type:** 5
- **Project period:** 2011-04-22 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927981

## Citation

> US National Institutes of Health, RePORTER application 9927981, Notch Signaling in Alloimmunity (5R01AI091627-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927981. Licensed CC0.

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