Elena Goleva, PhD, Leisa P. Jackson, BS, Melanie Gleason, PA, Donald Y

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Presentation transcript:

Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients Elena Goleva, PhD, Leisa P. Jackson, BS, Melanie Gleason, PA, Donald Y.M. Leung, MD, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 3, Pages 687-693.e1 (March 2012) DOI: 10.1016/j.jaci.2011.12.001 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Outline of study design. Asthmatic patients with an FEV1 percent predicted value of less than 80% were recruited into the study. Blood was drawn at the time of initial oral prednisone administration (visit 1) and 30 days after oral prednisone treatment (visit 3). The patients returned 7 days after oral prednisone treatment for spirometry (visit 2). At this visit, patients were defined as SR if less than 10% improvement in FEV1 percent predicted occurred and as SS if greater than 12% improvement in lung volume occurred. Glucocorticoid pharmacokinetics screening was done for all SR asthmatic patients. Only patients with a normal prednisone pharmacokinetics profile were included in the study. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 MKP-1 and IL-8 gene expression by PBMCs of SR and SS asthmatic patients, as detected by means of real-time PCR before (visit 1 [V1]) and 30 days after (visit 3 [V3]) prednisone burst. MKP-1 (A) and IL-8 (B) mRNA expression is significantly higher in freshly isolated PBMCs from SR than SS asthmatic patients at visit 1 but not visit 3. The difference between the SR and SS asthma groups was analyzed by using the nonparametric Mann-Whitney test. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Changes in the expression of steroid-regulated targets in PBMCs from SR and SS asthmatic patients after in vitro treatment with dexamethasone (DEX) before (visit 1 [V1]) and 30 days after (visit 3 [V3]) prednisone burst. Significantly reduced suppression of TNF-α (A) and IL-8 (B) mRNA by dexamethasone is observed in PBMCs from SR asthmatic patients than in PBMCs from SS asthmatic patients, as detected by means of real-time PCR at visit 1 but not visit 3. The difference between the SR and SS asthma groups was analyzed by using the unpaired t test. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 PBMCs from SR asthmatic patients compared with SS asthmatic patients require significantly more dexamethasone (DEX) to suppress PHA-induced T-cell proliferation at visit 1 (V1) but not visit 3 (V3). The difference between the SR and SS asthma groups was analyzed by using the nonparametric Mann-Whitney test. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 The expression of GCR isoforms in PBMCs from SR and SS asthmatic patients before (visit 1 [V1]) and 30 days after (visit 3 [V3]) prednisone burst, as detected by using real-time PCR. GCR-β (B), but not GCR-α (A), mRNA expression is significantly increased in freshly isolated PBMCs of SR asthmatic patients, resulting in a significantly lower molar ratio of GCR-α/GCR-β mRNA copies in the cells from SR asthmatic patients compared with that seen in SS asthmatic patients (C) at visit 1 but not visit 3. The difference between the SR and SS asthma groups was analyzed by using the nonparametric Mann-Whitney test. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 The composite score for steroid response assays in the SR and SS asthma groups before (visit 1 [V1]) and 30 days after (visit 3 [V3]) prednisone burst. The expression levels of the various individual targets used in this study (ie, MKP-1, IL-8, TNF-α fold suppression, IL-8 fold suppression, dexamethasone inhibitory concentration of 50% to suppress PHA-induced T-cell proliferation, GCR-β, and GCR-α/GCR-β ratio) was rank ordered into quartiles, and each value for the selected target was assigned a score of 1 through 4 depending on the quartile in which the value fit. A score of 1 was assigned for the least responsive quartile (ie, highest MKP-1, IL-8 baseline, GCR-β expression, dexamethasone inhibitory concentration of 50% for the suppression of the PHA-induced T-cell proliferation, lowest TNF-α, IL-8 fold suppression by dexamethasone, and lowest GCR-α/GCR-β ratio), and the score of 4 was given for the most responsive quartile. The scores for each target were summed, and a composite score was calculated. Because 7 targets were scored, 7 and 28 were considered the least and most steroid-responsive scores, respectively. The difference in composite score between the SR and SS asthma groups was calculated by using the exact permutation test. Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Dexamethasone (DEX) induction of BMPRII is not different in PBMCs of SR and SS asthmatic patients at visit 1 (V1) and visit 3 (V3). The difference between the SR and SS asthma groups was analyzed by using the unpaired t test). Journal of Allergy and Clinical Immunology 2012 129, 687-693.e1DOI: (10.1016/j.jaci.2011.12.001) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions