IPA: Mechanism of the Adrenal Stress Response Protection Against Therapy-induced Lethal Immune Activation

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. Public Health Relevance Statement The Veterans are under risk to develop blood cancers due to exposure to carcinogens, such as Agent Orange, during their active military service. Many of these cancers are treated with allo-HCT, however the successful outcome of transplant procedure is limited by the lethal immune activation caused by CRS. Completion of this study will provide a body of mechanistic and preclinical data for rapid clinical translation, which will improve the health of veterans.