Immunit innata ed adattativa nella patologia bronchiale Lorenzo - - PowerPoint PPT Presentation

Lorenzo Cosmi lorenzo.cosmi@unifi.it

Immunità innata ed adattativa nella patologia bronchiale

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Produzione di anticorpi

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Produzione di citochine etc

Tempo

• re

giorni

DC

• psonizzazione del

patogeno

Cooperazione tra immunità innata e acquisita

Annunziato F JACI 2015

The 3 major types of innate and adaptive cell-mediated effector immunity

Regulation of ILC2 by soluble-molecules and cell-to-cell receptors

Halim TYF Int Immunol 2015 Klose C Nat Immunol 2016

Increased numbers of activated ILC2 in the airways of patients with severe asthma and persistent airway eosinophilia

Smith SG L JACI 2016

Allergic rhinitis patients have increased recruitment of ILC2s to the upper airways following allergen challenge

Dhariwal J Am J Respir Crit Care Med 2017

Salimi M JEM 2013

Maggi L JACI 2017

Cosmi L Curr Allergy Asthma Rep 2017

Role of type 2 Innate Lymphoid Cells in asthma

Monoclonal antibodies that target ILC2 in asthma

Mitchell P Clin Pharmacol Ter 2016

In this double-blind, placebo-controlled study, we randomly assigned 31 patients with mild allergic asthma to receive three monthly doses

• f AMG 157 (700 mg) or placebo intravenously.

Treatment with AMG 157 reduced allergen- induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge.

Gauvreau G NEJM 2014

Corren J NEJM 2017

Among patients treated with long- acting beta-agonists and medium- to-high doses

• f

inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts

Tezepelumab in Adults with Uncontrolled Asthma

CRTH2 antagonist in the treatment of eosinophilic asthma

Gonem S Lancet Respir Med 2016

Multiple targets of prostaglandin D2 receptor antagonists

Cosmi L Am J Respir Crit Care Med. 2017

Varricchi G Curr Opin Allergy Clin Immunol 2016

Mepolizumab and Reslizumab bind IL-5, whereas Benralizumab binds IL-5Rα

IL-33 selectively licensed memory Th2 cells to induce allergic airway inflammation via production

• f IL-5 and the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory

Th2 cells.

IL-33 induces selective remodeling of chromatin at the Il5 Locus in memory Th2 Cells

Endo Y Immunity 2015

In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population Brown KR PLoS One 2017

135 patients with severe eosinophilic asthma, treated with mepolizumab administered subcutaneously every 4 weeks for 20 weeks. Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, had a relative reduction of 32% in the annualized rate

• f exacerbations.

576 patients with recurrent asthma exacerbations and evidence

• f

eosinophilic inflammation despite high doses of inhaled glucocorticoids Patients were assigned to receive mepolizumab, either a 75-mg intravenous dose or a 100- mg subcutaneous dose, or placebo every 4 weeks for 32 weeks

Bel EH NEJM 2014 Ortega HG NEJM 2014

Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate

• r severe exacerbations than placebo among patients with COPD and an eosinophilic
• phenotype. This finding suggests that eosinophilic airway inflammation contributes to

COPD exacerbations.

Pavord ID NEJM 2017

Mepolizumab for Eosinophilic COPD

IL-4/IL-13 receptors and signaling pathways

Ingram J JACI 2012

Mechanism of action of Dupilumab

Dupilumab binds to the IL-4α chain prohibiting either IL-4 or IL-13 from binding and subsequent signaling through the STAT6 pathway

Casale T JACI 2017

Wenzel S Lancet 2016 Total Eosinophils > 300 Eosinophils < 300

Dupilumab effects in uncontrolled persistent asthma

Cosmi L Allergy 2011

Th17 lymphocytes: new players in asthma pathogenesis

Possible role of different T-cell subsets in the pathogenesis of asthma and COPD

Cosmi L Curr Opin Allergy Clin Immunol 2016

Brodalumab binds human interleukin-17RA and blocks the biologic activity of interleukins 17A, 17F, 17A/F heterodimer, 17C and 17E (interleukin-25)

Nirula A Rheumatology 2017

Brodalumab blocks both IL-17A and IL-25

Brodalumab has been tested in patients with severe asthma, although patients with neutrophilia were unfortunately not selected for this study Conclusions: Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. The results of the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation.

Busse W et al. Am J Resp Crit Care Med 2013

Concluding remarks

• Biologicals targeting both innate and adaptive immunity are effective in type 2

inflammation in bronchial asthma if patients are selected on the basis of their asthma

• phenotype. Despite stratification, in non-type 2 asthma and in COPD the results of

targeted therapy have proved disappointing.

Bel E Chest 2017

Center for Research “DENOTHE”

• Dept. of Clinical &

Experimental Medicine Raffaele De Palma

• Dept. of Paediatrics,

Rheumatology Unit Rolando Cimaz Laura Maggi Alessio Mazzoni Manuela Capone Veronica Santarlasci Maria Caterina Rossi Gianni Montaini Beatrice Rossettini Paola Parronchi Oliviero Rossi Andreas Radbruch Hyun-Dong Chang Jun Dong Dipartimento di Patologia e Diagnostica Marco Cassatella Francesco Annunziato Sergio Romagnani Enrico Maggi Francesco Liotta