# Mechanism of the adrenal stress response protection against therapy-induced lethal immune activation

> **NIH VA I01** · VA MEDICAL CENTER - LEXINGTON, KY · 2024 · —

## Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy
for hematologic malignancies and other diseases, in which the donor's stem cells are
used to replace the recipient's damaged or destroyed cells. The Veterans Health
Administration has been offering allo-HCT services since 1982, which have saved
thousands of veterans' lives. However, this life-saving therapy comes at a cost - lethal
immune activation caused by cytokine release syndrome (CRS). Currently,
glucocorticoids (GC) and IL-6 antagonists are used for CRS treatment, but some
patients do not respond well to treatment. A limitation is that CRS may cause
irreversible organ injury before treatment is initiated, as the indicator of treatment is
CRS itself. Therefore, there is an urgent need to identify patients at high risk of CRS
and provide preventive therapy.
 We recently reported that the adrenal stress response, defined by a 6-fold
increase in induced GC (iGC) production, is an essential host response against therapy-
induced lethal immune activation. We identified scavenger receptor BI (SR-BI), an HDL
receptor, as a key regulator for iGC production. Using SR-BI null mice as an adrenal
stress response deficiency model, we demonstrated that the adrenal stress response
protects against therapy-induced death by controlling CRS. Conversely, relative adrenal
insufficiency (RAI) - the absence of adrenal stress response - is a risk factor for CRS.
Our study provides proof-of-concept that diagnosing RAI may help identify patients at
risk of CRS, and selective GC therapy for patients with RAI prior to the onset of CRS
may reduce mortality from therapy-induced lethal immune activation. The goal of this
application is to delineate the mechanisms of the adrenal stress response protection
against CRS in allo-HCT-induced lethal immune activation and to translate the
mechanistic findings into a precision medicine approach to prevent CRS in allo-HCT-
induced lethal immune activation.

## Key facts

- **NIH application ID:** 10804993
- **Project number:** 1I01BX006408-01
- **Recipient organization:** VA MEDICAL CENTER - LEXINGTON, KY
- **Principal Investigator:** XIANG-AN LI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804993

## Citation

> US National Institutes of Health, RePORTER application 10804993, Mechanism of the adrenal stress response protection against therapy-induced lethal immune activation (1I01BX006408-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804993. Licensed CC0.

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