Targeting CYP11A1 in the Steroidogenic Pathway For Treating Allergic Diseases
NJH ID: #11-17
CD4 Th2 and CD8 Tc2 cells play a pivotal role in the induction and control of allergic inflammation, including food allergy and asthma. 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.
Glucocorticoids (GCs) play an important role in the regulation of the immune system. Because of their anti-inflammatory activity GCs are 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. This particular enzyme converts cholesterol to pregnenolone.
Dr. Gelfand’s laboratory has identified CYP11A1 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 the polarization of CD8+ T cells from an IFN-γ to an IL-13 producing effector cell. Therefore CYP11A1 is a critical regulator of the development of lung allergic responses.
In vitro, both human and mouse CD8+ T cells demonstrated an insensitivity to corticosteroids not seen in CD4+ T cells, supporting the notion that CD8+ T cells are at the root of the failure of asthmatics to respond to corticosteroids and could be responsible for persistent airway hyperresponsiveness (AHR) and airway inflammation.
Gene silencing of CYP11A1 also prevented CD4 Th2 and CD8 Tc2 differentiation.
In a mouse model of peanut allergy, treatment with aminoglutethimide (AMG), an inhibitor of CYP11A1, prevented an allergic response and the accumulation of inflammatory cells in a dose dependent manner. Serum levels of pregnenolone were reduced in parallel.
In an experimental model of asthma, adoptive transfer of AMG-treated CD8+ T cells to sensitized and challenged CD8+ deficient mice prevented AHR and inflammation, in contrast to untreated CD8+ T cells.
These studies identified CYP11A1 as a key regulator of CD8+ Tc2 cell differentiation and plasticity and as a valuable target in the treatment of allergic diseases such as asthma and peanut allergy.
Treatment or prevention of allergic diseases by administration of CYP11A1 inhibitors such as AMG.
State of Development
Investigators are currently screening libraries to identify molecules that will inhibit CYP11A.
Wang, Meiqin, Julita Ramirez, Junyan Han, Yi Jia, Joanne Domenico, Max A. Seibold, James R. Hagman, and Erwin W. Gelfand. "The Steroidogenic Enzyme Cyp11a1 Is Essential for Development of Peanut-induced Intestinal Anaphylaxis." Journal of Allergy and Clinical Immunology 132.5 (2013): 1174-183.e8 - PMID: 23870673
Jia, Y., J. Domenico, K. Takeda, J. Han, M. Wang, M. Armstrong, N. Reisdorph, B. P. O'connor, J. J. Lucas, and E. W. Gelfand. "Steroidogenic Enzyme Cyp11a1 Regulates Type 2 CD8 T Cell Skewing in Allergic Lung Disease." Proceedings of the National Academy of Sciences 110.20 (2013): 8152-157. – PMID: 23630275
US and International patents pending. US patent application 20140206749
Erwin Gelfand, MD, Meiquin Wang, MD, Ph.D. and Yi Jia.
This technology is available for licensing.
For Further Information, Contact:
Emmanuel Hilaire, PhD
Technology Transfer Office
National Jewish Health
1400 Jackson St., Room M206b
Denver, CO 80206