Dataset Information

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis.

ABSTRACT:

Background

Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway, converting cholesterol to pregnenolone. Cyp11a1 expression is increased in activated T cells.

Objectives

We sought to determine the role of Cyp11a1 activation in the development of peanut allergy and TH cell functional differentiation.

Methods

A Cyp11a1 inhibitor, aminoglutethimide (AMG), was administered to peanut-sensitized and challenged mice. Clinical symptoms, intestinal inflammation, and Cyp11a1 levels were assessed. The effects of Cyp11a1 inhibition on T(H)1, T(H)2, and T(H)17 differentiation were determined. Cyp11a1 gene silencing was performed with Cyp11a1-targeted short hairpin RNA.

Results

Peanut sensitization and challenge resulted in diarrhea, inflammation, and increased levels of Cyp11a1, IL13, and IL17A mRNA in the small intestine. Inhibition of Cyp11a1 with AMG prevented allergic diarrhea and inflammation. Levels of pregnenolone in serum were reduced in parallel. AMG treatment decreased IL13 and IL17A mRNA expression in the small intestine without affecting Cyp11a1 mRNA or protein levels. In vitro the inhibitor decreased IL13 and IL17A mRNA and protein levels in differentiated T(H)2 and T(H)17 CD4 T cells, respectively, without affecting GATA3, retinoic acid-related orphan receptor ?t (ROR?t), or T(H)1 cells and IFNG and T-bet expression. Short hairpin RNA-mediated silencing of Cyp11a1 in polarized T(H)2 CD4 T cells significantly decreased pregnenolone and IL13 mRNA and protein levels.

Conclusion

Cyp11a1 plays an important role in the development of peanut allergy, regulating peanut-induced allergic responses through effects on steroidogenesis, an essential pathway in T(H)2 differentiation. Cyp11a1 thus serves as a novel target in the regulation and treatment of peanut allergy.

SUBMITTER: Wang M

PROVIDER: S-EPMC3864874 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis.

Wang Meiqin M Ramirez Julita J Han Junyan J Jia Yi Y Domenico Joanne J Seibold Max A MA Hagman James R JR Gelfand Erwin W EW

The Journal of allergy and clinical immunology 20130716 5

<h4>Background</h4>Cytochrome P450, family 11, subfamily A, polypeptide 1 (Cyp11a1), a cytochrome P450 enzyme, is the first and rate-limiting enzyme in the steroidogenic pathway, converting cholesterol to pregnenolone. Cyp11a1 expression is increased in activated T cells.<h4>Objectives</h4>We sought to determine the role of Cyp11a1 activation in the development of peanut allergy and TH cell functional differentiation.<h4>Methods</h4>A Cyp11a1 inhibitor, aminoglutethimide (AMG), was administered ...[more]

PMID: 23870673

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Project description:Importance:Children experiencing anaphylaxis at school may lack access to a personal epinephrine device, prompting recent legislation permitting undesignated (eg, non-student specific) stock epinephrine autoinjector units at school. However, epinephrine device costs vary, and the cost-effectiveness of undesignated school stock epinephrine is uncharacterized to date. Objective:To define value-based strategies for undesignated school stock epinephrine programs. Design, Setting, and Participants:Markov simulations of the Chicago Public Schools system were used over extended time horizons to model 2 school stock epinephrine autoinjector policies to provide access for at-risk students. The dates of the data used in the analysis were September 2017 to June 2018 (the 2017-2018 school year). Main Outcomes and Measures:This study compared the following 3 strategies: no school undesignated epinephrine supply, school undesignated supplemental epinephrine supply (supplemental model), and school undesignated universal epinephrine supply (universal model). The base-case model assumed a 10-fold reduced fatality risk with having undesignated stock epinephrine units available vs not having undesignated stock epinephrine units available. Costs of school stock epinephrine units available for acquisition by schools were evaluated from a societal perspective. Quality-adjusted life-years (QALYs) and total epinephrine acquisition expenses were calculated. Results:Based on Markov simulations of the Chicago Public Schools system (371 382 students), the cost was $107 816 (95% CI, $107 382-$108 250) for no school undesignated epinephrine supply compared with $108 160 (95% CI, $107 725-$108 595) for the supplemental model and $100 397 (95% CI, $99 979-$100 815) for the universal model. Undesignated stock epinephrine improved outcomes, with 26.869 (95% CI, 26.841-26.897) QALYs accrued as the model concluded compared with 26.867 (95% CI, 26.839-26.896) QALYs for the strategy without undesignated stock epinephrine. When comparing supplemental model stock epinephrine to the strategy without undesignated devices, the incremental cost-effectiveness ratio was high at $268 811 per QALY in the base-case simulation. However, the cost of the supplemental model fell below $100 000 per QALY when the annual undesignated epinephrine acquisition costs did not exceed $338 per school (compared with stock epinephrine unavailability). The universal model dominated all others and was associated with significant cost savings ($7419 per student at risk who would otherwise be prescribed an individual school epinephrine supply). Conclusions and Relevance:Undesignated school stock epinephrine is cost-effective at device acquisition costs not exceeding $338 per school per year, although a universal model vs a supplemental model is associated with superior health and economic outcomes.

Dataset Information

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis.

Background

Objectives

Methods

Results

Conclusion

Publications

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis.

Similar Datasets

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