PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4 + T cell function

Journal of Translational Medicine

A Hamid Boulares⁴  Amarjit S Naura²  Augusto Ochoa⁴  Alistair Ramsay¹  Kamel Al-Ghareeb⁵  Moselhy S Mansy⁵  Matthew R Lammi⁶  Ali H El-Bahrawy⁴  Hamada F Rady¹  Paulo Rodriguez⁴  Jeffrey Wang⁴  Amir A Al-Khami³  Salome V Ibba⁴  Kusma Pyakurel⁴  Mohamed A Ghonim⁵ 

[1] Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA;Department of Biochemistry, Panjab University, Chandigarh, India;Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt;The Stanley Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans 70112, LA, USA;Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;Pulmonary and Critical Care Section, School of Medicine, Louisiana State University, New Orleans, LA, USA

关键词: Allergen-specific IgE;    Th2 cytokines;    Adoptive transfer;    Allergen-induced eosinophilia;    Olaparib (AZD2281);    PARP inhibition;   

Others  :  1221463
DOI  :  10.1186/s12967-015-0583-0

 received in 2015-04-16, accepted in 2015-06-25,  发布年份 2015

【 摘 要 】

Background

An important portion of asthmatics do not respond to current therapies. Thus, the need for new therapeutic drugs is urgent. We have demonstrated a critical role for PARP in experimental asthma. Olaparib, a PARP inhibitor, was recently introduced in clinical trials against cancer. The objective of the present study was to examine the efficacy of olaparib in blocking established allergic airway inflammation and hyperresponsiveness similar to those observed in human asthma in animal models of the disease.

Methods

We used ovalbumin (OVA)-based mouse models of asthma and primary CD4 ⁺T cells. C57BL/6J WT or PARP-1 ^−/−mice were subjected to OVA sensitization followed by a single or multiple challenges to aerosolized OVA or left unchallenged. WT mice were administered, i.p., 1 mg/kg, 5 or 10 mg/kg of olaparib or saline 30 min after each OVA challenge.

Results

Administration of olaparib in mice 30 min post-challenge promoted a robust reduction in airway eosinophilia, mucus production and hyperresponsiveness even after repeated challenges with ovalbumin. The protective effects of olaparib were linked to a suppression of Th2 cytokines eotaxin, IL-4, IL-5, IL-6, IL-13, and M-CSF, and ovalbumin-specific IgE with an increase in the Th1 cytokine IFN-γ. These traits were associated with a decrease in splenic CD4 ⁺T cells and concomitant increase in T-regulatory cells. The aforementioned traits conferred by olaparib administration were consistent with those observed in OVA-challenged PARP-1 ^−/−mice. Adoptive transfer of Th2-skewed OT-II-WT CD4 ⁺T cells reversed the Th2 cytokines IL-4, IL-5, and IL-10, the chemokine GM-CSF, the Th1 cytokines IL-2 and IFN-γ, and ovalbumin-specific IgE production in ovalbumin-challenged PARP-1 ^−/− mice suggesting a role for PARP-1 in CD4 ⁺T but not B cells. In ex vivo studies, PARP inhibition by olaparib or PARP-1 gene knockout markedly reduced CD3/CD28-stimulated gata-3 and il4 expression in Th2-skewed CD4 ⁺T cells while causing a moderate elevation in t-bet and ifn-γ expression in Th1-skewed CD4 ⁺T cells.

Conclusions

Our findings show the potential of PARP inhibition as a viable therapeutic strategy and olaparib as a likely candidate to be tested in human asthma clinical trials.

【 授权许可】

   
2015 Ghonim et al.

【 图 表 】

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