Back to Search
Start Over
PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4+ T cell function
- Source :
- Journal of Translational Medicine
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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.
- Subjects :
- CD4-Positive T-Lymphocytes
Adoptive cell transfer
Chemokine
Allergen-specific IgE
Immunoglobulin E
Piperazines
Gene Knockout Techniques
chemistry.chemical_compound
0302 clinical medicine
Olaparib (AZD2281)
Medicine(all)
0303 health sciences
biology
Adoptive transfer
General Medicine
3. Good health
030220 oncology & carcinogenesis
PARP inhibitor
Cytokines
Bronchial Hyperreactivity
Poly(ADP-ribose) Polymerases
Ovalbumin
GATA3 Transcription Factor
Poly(ADP-ribose) Polymerase Inhibitors
General Biochemistry, Genetics and Molecular Biology
Olaparib
Allergen-induced eosinophilia
03 medical and health sciences
Th2 Cells
Antigen
Antigens, CD
Eosinophilia
Animals
Humans
Interleukin 4
030304 developmental biology
Biochemistry, Genetics and Molecular Biology(all)
Research
PARP inhibition
Th1 Cells
Asthma
Mice, Inbred C57BL
Disease Models, Animal
Mucus
chemistry
Immunology
biology.protein
Phthalazines
Th2 cytokines
T-Box Domain Proteins
Spleen
Subjects
Details
- ISSN :
- 14795876
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Journal of Translational Medicine
- Accession number :
- edsair.doi.dedup.....7dd75fee80cd5b9de201a233595ce42c