Targeting CYP11A1 in the Steroidogenic Pathway for Treating Allergic Diseases
National Jewish Health
CD4 Th2 and CD8 Tc2 cells play a pivotal role in the induction and control of allergic inflammation, including food allergy and asthma. In humans, allergen-specific Th2 CD4+ T cells are essential to the development and maintenance of both type I IgE-mediated and non-IgE-mediated food allergic responses. Steroid hormones, such as glucocorticoids (GCs), are part of a feedback mechanism that plays an important role in the regulation of the immune system. The anti-inflammatory activity of GCs is well described and this property is used to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis. There is accumulating evidence suggesting that GCs can also promote the pathogenesis of allergic diseases by enhancing T-cell pro-allergic differentiation of CD4+T cells to Th2 and Th17, by amplifying immune responses in steroid-insensitive CD8+ T cells and by inhibiting Th1 cytokine production. Endogenous GC synthesis is regulated by the transcriptional control of steroidogenic enzymes of the cytochrome P450 gene family, such as CYP11A1.
Dr. Gelfand’s laboratory has identified CYP11A1, a member of the cytochrome P450 superfamily of enzymes that converts cholesterol to pregnenolone, as a key regulator of allergic responses through its effect on steroidogenesis. They demonstrated that CYP11A1 controls the phenotypic conversion of CD4+T cells to Th2 and Th17 and CD8+ T cells from INF-g to IL-13 producing cells, linking steroidogenesis to a pro-allergic differentiation pathway.Inhibition of CYP11A1 with aminoglutethimide in an animal model of peanut allergy prevented an allergic response and the accumulation of inflammatory cells in a dose dependent manner. Gene silencing of CYP11A1 prevented CD4 Th2 and CD8 Tc2 differentiation. Levels of cortisol were reduced in parallel. The data collected indicate that CYP11A plays an important role in the development of allergy and that the therapeutic approach seen in peanut allergy could be applicable to other allergic diseases.
Treatment or prevention of allergic diseases by administration of CYP11A1 inhibitors such as aminoglutethimide
State of Development
Investigators are currently screening libraries to identify molecules that will inhibit CYP11A.
- Wang et al. (2013) J. Allergy Clin Immunol. 131(2) Supplement: Page AB143
US and International patents pending.
Erwin Gelfand, MD, Meiquin Wang, MD, Ph.D. and Yi Jia
This technology is available for licensing.