# IL-33 Blockade as a Novel Therapeutic for T-cell Mediated Hypercytokinemia Syndromes

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $586,684

## Abstract

Project Summary:
A number of inflammatory diseases result from excessive cytokine production (hypercytokinemia), with an
important subset of these driven by inappropriate or excessive T-cell activation. Two examples of T-cell-
mediated hypercytokinemia syndromes include Familial Hemophagocytic Lymphohistiocytosis (FHL) and bone
marrow transplantation (BMT)-associated graft-versus-host disease (GVHD). In FHL, hypercytokinemia is
directly responsible for organ failure and death, and yet some degree of cytokinemia is still needed for control
of the triggering infections. For BMT, the toxicity of hypercytokinemia represents a major limitation for its
clinical use in treating cancer. As limited options are available for treatment of T-cell-mediated
hypercytokinemia, identification of new therapeutic strategies is necessary. This could be challenging in T-cell-
mediated hypercytokinemia induced by allogeneic BMT therapy, where the anti-tumor and cytokine-producing
effects of T cells need to be separated.
 Since TCR signaling blockade would likely lead to simultaneous abrogation of cytokine production and
anti-tumor cytotoxicity, targeting a non-TCR signaling pathway that is involved only in T cell cytokine release
may represent a novel strategy. Furthermore for FHL, targeting a pathway that does not completely block
cytokine production, but rather restores it to normal protective levels is desirable. We hereby propose that the
IL-33 signaling is a common mechanism that exacerbates T-cell-mediated hypercytokinemia syndromes via a
non-TCR mechanism. IL-33 is an “alarmin”, a molecule released upon tissue damage that can modulate
immune responses. Our data show that ST2 signaling increases IFN production by CD8+ T cells and that IL-
33 is required for FHL and GVHD pathogenesis. Thus, we hypothesize that IL-33 derived from damaged cells
is critical for T-cell-mediated hypercytokinemia by enhancing the pathogenic IFN T-cell response without
affecting cytotoxic anti-tumor responses. In this proposal, we will define the cellular and molecular mechanisms
by which IL-33 contributes to T-cell-mediated hypercytokinemia and uncover the source and inducing factors of
IL-33 using 2 separate clinically relevant models of T-cell-mediated hypercytokinemia. Our studies include both
the investigation of the mechanisms by which IL-33 promotes disease pathogenesis in animal models as well
as correlating these findings to human patients with these diseases. Armed with this information, we will be
poised to develop the best strategy for IL-33 blockade in T cell-mediated hypercytokinemia syndromes, with
the potential to reduce mortality and morbidity in these devastating complications.

## Key facts

- **NIH application ID:** 9926221
- **Project number:** 5R01AI121250-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** EDWARD M BEHRENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,684
- **Award type:** 5
- **Project period:** 2016-06-08 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926221

## Citation

> US National Institutes of Health, RePORTER application 9926221, IL-33 Blockade as a Novel Therapeutic for T-cell Mediated Hypercytokinemia Syndromes (5R01AI121250-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926221. Licensed CC0.

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