In vitro models for assessment of the respiratory sensitization potential of compounds.

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1 In vitro models for assessment of the respiratory sensitization potential of compounds. 1 Investment driving Animal-free Testing

2 Setting the scene 2

3 What we know about skin sensitization induction in a nutshell. 1. Bioavailability Stratum corneum 2. Haptenation Lys, Cys 3. Epidermal inflammation TLR, ROS, HA, Inflammasome, Nfr2, IL Dendritic cell activation and maturation Specific gene sets, CD86, CD54 5. Dendritic cell migration Fibroblasts, CXCL12/CXCR4, CCL19/21, CCL2, CCL5 6. T-cell proliferation T h 1, T h 17 Adler et al. (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects Arch. Toxicol. DOI: /s Roggen (2014) In vitro approaches for detection of chemical sensitization. Basic Clin. Pharmacol. Toxicol. DOI: /bcpt (minireview) 3

4 What we know about skin lung sensitization induction in a nutshell. 1. Bioavailability Mucus, surfactant Stratum corneum 2. Haptenation Lys, Cys 3. Epidermal inflammation TLR*, ROS, HA, Inflammasome, Nfr2*, IL-18* 4. Dendritic cell activation and maturation Specific gene sets, CD86, CD54 5. Dendritic cell migration Fibroblasts, CXCL12/CXCR4, CCL19/21, CCL2, CCL5 6. T-cell proliferation T h 2 T h 1, T h 17 Wills-Karp et al. (2010) New insights into innate mechnasims underlying allergenicity. Mucosal Immunol. 3:104. DOI: /mi Roggen (2014) In vitro approaches for detection of chemical sensitization. Basic Clin. Pharmacol. Toxicol. DOI: /bcpt (minireview) 4

5 Bioavailability ASSESSING THE ACCESSABILITY OF EXPOSING COMPOUNDS TO VIABLE CELLS 5

6 A human cell based assay for pulmonary absorption Correlated to lipophilicity, the molecular polar surface area, and hydrogen bond donor counts (in vivo, QSAR, in vitro) Reconstituted human bronchial and nasal epithelium MucilAir TM, Epithelix Sárl 30 compounds Apical and basolateral exposure Non-toxic concentrations, Different timepoints Read-out: permeability rate (P app ) 3 laboratories Epithelix Sárl, University of Geneva, EURL-ECVAM High reproducibility Within and between laboratories (CV=15%) Reus et al. (2014) Feasibility of a 3D human airway epithelial model to study respiratory absorption. Toxicol. In Vitro. 28;

7 Haptenation INNATE RECOGNITION OF FOLLOWED BY ACTIVATION OF INNATE IMMUNITY 7

8 The Direct Peptide Reactivity Assay provides qualified information about the capacity of a chemical to induce sensitization. Mechanism of action Quantification by HPLC-UV of peptide depletion 1. ESAC recommendation published Both Cys and Lys reactive compounds Not useful for mixtures 2. Adapted to prohaptens (not validated) 3. Widely used within the cosmetic and chemical industry 8

9 Inflammation INNATE RECOGNITION OF FOLLOWED BY ACTIVATION OF INNATE IMMUNITY - Epithelial cells orchestrating dendritic cells - 9

10 IL-8 (pg/ml) Compound In Vitro lung epithelial tissue is more responsive to chemical respiratory sensitizers. Cytokine MDI IL-8 ++ IL-6 ++ MCP-1 ++ HCPt IL-8 ++ IL-6 ++ MCP-1 - DNCB IL-8 +/- IL-6 +/- MCP-1 - SA IL-8 - IL-6 - MCP-1 - Reconstituted alveolar-endothelial model (University of Mainz) Reconstituted bronchial model (Epithelix Sàrl) PCLS (Fraunhofer ITEM) Eotaxin GM-CSF IL-1 IL-2 IL-4 IL-5 IL-6 IL-8 IL-10 Il-12 MCP-1ß MIP-1ß RANTES TNF- (+)control: LPS Respiratory Skin (-) control

11 Protein-induced responses are defined by the functionality % Effect of Amylase on Tissue Integrity, Cytotoxicity and Cell Viability - after 6 days recovery % TEER [ohm.cm2] TEER [ohm.cm2] % of Cytotoxicity TEER [ohm.cm2] % of Cytotoxicity and Viability M-CSF (pg/ml) PROTEASE LIPASE Wills-Karp et al. (2010) New insights into innate mechnasims underlying allergenicity. Mucosal Immunol. 3:104. DOI: /mi Effect of Amylase on Tissue Integrity and Cytotoxicity - after 24h exposure - M-CSF strem-1, PAI-1, MIF-1, CXCL11, IL-1ɑ, IFN-γ, CD54, CD154, CD5a TNF-ɑ; CXCL12; IL-16; IL-8; IL-1ß IL-32a; IL-12p70; IL-10; CCL-5 CCL-2 IL-23 IL-17E IL-6 G-CSF AMYLASE Amylase [mg/ml] 150% 120% 90% 60% 30% Effect of Protease on Tissue Integrity and Cytotoxicity - after 24h exposure Protease [mg/ml] 0% TEER % of Cytotoxicity Cytotoxicity 180% 150% 120% 90% 60% 30% 0% TEER Cytotoxicity TEER [ohm.cm2] Amylase [mg/ml] Protease [mg/ml] 150% 120% 90% 60% 30% Effect of Protease on Tissue Integrity, Cytotoxicity and Cell Viability - after 6 days recovery % 0% 90% 60% 30% 0% TEER 150% 120% % of Cytotoxicity and Viability Cytotoxicity Viability TEER Cytotoxicity Viability ,001 0,01 0, mg protease/ml Protease 1 Protease 2 Protease 3 11

12 Dendritic cell activation and maturation FROM INNATE RESPONSES TO MATURATION 12

13 A predictive biomarker assay for prediction of sensitization Sensitizing chemical induction of specific signaling pathways by sensitizers Non-sensitizing chemical 13

14 Genomic Allergen Rapid Detection (GARD) test Assay performance: a. One concentration 1. Cytotoxic and soluble: RV90 2. Non-cytotoxic and soluble: <500 µm 3. Low solubility: highest soluble concentration b. One time point 24 hours Predefined phenotype c. Repetitions At least duplicates in two independent experiments Johansson, et al. (2011) A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. BMC Genomics 2011; 12:

15 Establishing a Prediction Signature ~29000 genes P-value filtering 1000 genes Backward Elimination Sensitizer Non - sensitizer Accuracy: 39 / % Sensitivity: 19 / 20 95% Specificity: 20 / %

16 Skin, chemical respiratory and proteinaceous sensitizers tell their own story. MUTZ-3 cell line 200 genes 80 compounds tested > 90% accuracy Successfully assessed by industry Approved by ECVAM for further evaluation MUTZ-3 cell line 300 genes 10 compounds tested > 80% accuracy MUTZ-3 cell line 300 genes 21 compounds tested 100% accuracy (???) 16 SenzaGen

17 Correlating potency prediction to pathway usage also for the lung? Max Min chemical reactivity groups Strong Weak Albrekt et al (2013) Differentially regulated signalling pathways in MUTZ-3 cells stimulated with skin sensitizers. BMC Pharmacol. Toxicol. 2014; 15:5 ( 17

18 Phenotype changes related to maturation Property Immature Mature MHC class I CD44 +/- +++ CD54 +/- +++ CD58 +/- +++ CD CD CD Il CCR1,2,5, CCR CXCR E-cadherin Ag capture Ag processing Ag presentation Wang et al. (1999) J. Leukoc. Biol. 66:

19 In Vitro Dendritic cell maturation Maturation markers THP-1 cell line CD54 + CD86 (h-clat) U937 cell line CD86 (MUSST) *** Test performance Number of test chemicals: >100 Concordancy: 80% No potency information (yet) ***: prevalidation study stopped 19

20 Dendritic cell migration BRINGING THE MESSAGE TO THE LYMPHOID TISSUE 20

21 Understanding of the mechanisms driving DC migration during sensitization is most advanced for the skin. An important role for fibroblasts and other dermis-derived stromal cells, and in particular CXCL12/CXCR4, in mediating LC migration. Ouwehand et al. (2008) CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur. J. Immunol. 2008; 38: Ouwehand et al. (2011) Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration. Technical Advance 2011; 90: Ouwehand et al. (2012) Migration of immature Langerhans cells upon topical irritant exposure is dependent on CCL2 and CCL5. Eur. J. Immunol. 2012; 40: Human dermal fibroblasts are the source of dermal chemo-attractants (CCL2 and CCL5) in the migration of still immature LCs out of the epidermis and into the dermis after exposure to contact irritants. A full-thickness tissue-engineered skin model containing fully functional MUTZ-3 derived LCs 21

22 Guided by fibroblasts dendritic cells discriminate sensitizers and irritants. CSFE-labeled MUTZ-LC Sensitizer CXCR4+ CCR5+ CXCR4+ CCR5+ rec-cxcl12 (sensitisers) rec-ccl5 (non-sensitisers) 22

23 Guided by fibroblasts dendritic cells discriminate sensitizers and irritants. CSFE-labeled MUTZ-LC Irritant CXCR4+ CCR5+ CXCR4+ CCR5+ rec-cxcl12 (sensitisers) rec-ccl5 (non-sensitisers) 23

24 CXCL12/CCL5 ratio In Vitro Dendritic cell migration does not discriminate skin and lung sensitizers MUTZ-3 cell line 12 compounds tested 100% accuracy (???) Successfully assessed by industry Approved by ECVAM for further evaluation 24

25 Conclusion 25

26 Novel testing method for assessment of pulmonary sensitization The assays are functional but predictive accuracy to be evaluated. Skin and respiratory sensitizers (including proteins) behave different in pulmonary models but seem to play the same mechanisms. Th1 Th2 skewing: Where and how? o o Characteristics of the chemical and/or the targetted protein? IL-18 & Co versus M-CSF, ATP, uric acid & Co? The holistic approach of using genomic biomarkers allows for readouts with high informational content. New information about the effect of protein target selectivity (supported by proteomics) Opportunities for expanding the functionality of the assay Multiple end-points (Contact and respiratory sensitizers, irritants, genotoxicants) Mechanisms of action (Potency assessment) Better understanding the mechanisms defining potency Target protein identification / amino acid selection Pathway analysis and marker signature identification Quantitative relation between marker signatures and potency of a chemical 26

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