Mechanistic aspects of in vivo and in vitro testing of allergic agents
1
Abstracts / Toxicology Letters 189S (2009) S37–S56 S45 nocarcinomas in the lungs was observed. The causal role of the inflammatory effects in the chronic pathogeneses developing in this mouse model and their relevance to human smoking-related diseases remain to be established. Acknowledgement: Supported by Philip Morris International and Philip Morris USA. doi:10.1016/j.toxlet.2009.06.118 W05-05 Mechanistic aspects of in vivo and in vitro testing of allergic agents Christian Martin Pharmacology and Toxicology, University Hospital Aachen, Aachen, Germany A wide range of industrial chemicals can induce respiratory allergic reactions. At present, there are no widely applied or fully validated test methods to identify respiratory allergens, i.e., compounds that are considered capable of inducing allergic asthma. Hence, there is an urgent need for methods identifying and characterizing the biological action of chemicals in the lung. To discriminate and clas- sify the allergic potential of the different compounds, several in vivo and in vitro models were utilized. In order to test rather low doses of chemicals in vivo, various methods, different application routes, i.e., intradermal, topical or inhalation exposure, different duration and several species, i.e., guinea pig, rat or mouse were used. In vivo physiological parameters like respiratory functional response (specific or unspecific), tests in lymph nodes, and cel- lular response in B- and T-cells, macrophages and epithelial cells were performed. In addition reliable alternative ex vivo and in vitro methods are to claim. In primary epithelial cells, B- and T-cells, and dendritic cells and different cell lines structural cell changes, expression and release of proteins and mediators (like TH1 and TH2 cytokines) were monitored to determine the ability of com- pounds to provoke allergy. As the lung consists of more then 40 different cell types, respiratory allergens are hard to define in sin- gle cell types. Viable lung slices represent an alternative method to test functional and immunological responses to chemical compounds. Herein, an overview of the different methods and their mech- anistic responses to the industrial chemicals trimellitic anhydride (TMA) and 2,4-dinitrochlorobenzene (DNCB) is given. doi:10.1016/j.toxlet.2009.06.119 W05-06 Lung fibrosis is uncoupled from inflammation in response to toxic nano- and micro-particles Francois Huaux ∗ , Sandra Lo Re, Marylène Lecocq, Virginie Rabolli, Giulia Giordano, Julie Muller, Virginie Barbarin, Dominique Lison Université catholique de Louvain, Unit of Industrial Toxicology, Brussels, Belgium The paradigm that inflammation drives pulmonary fibrosis has been recently challenged. We observed that nano- and micro-particle-induced lung fibrosis in animals was unpaired to inflammation. The fibrotic disease was also resistant to several anti-inflammatory therapies and occurred in mice deficient for pro-inflammatory cytokines (i.e., IL-1, IL-12p35, IL-17 and type I IFN). Interestingly, silica-induced lung fibrosis in mice was charac- terized by a chronic anti-inflammatory response accompanied by macrophage-derived anti-inflammatory cytokine overexpression (i.e., IL-10, soluble TNF- receptors and TGF-). We showed that IL- 10 (like TGF-) has a detrimental activity during the establishment of lung fibrosis despite its capacity to control certain macrophage functions and the inflammatory process. IL-10 deficient or over- expressing mice developed reduced or enhanced silica-induced lung fibrosis, respectively. The profibrotic activity of IL-10 in vivo appeared to be mediated by its ability to stimulate the expression of TGF-1 while suppressing the expression of cyclooxygenase- 2 and thus production of the anti-fibrotic eicosanoid PGE2. The anti-inflammatory pathway associated with silica-induced fibrotic lesions in mice was not restricted to macrophages since immunosuppressive regulatory T cells, estimated by Foxp3 lung expression, were also accumulated during the development of lung fibrosis. In conclusion, a pronounced anti-inflammatory reaction may also contribute to particle-induced lung fibrosis and represent an additional etiopathogenic pathway of lung fibrosis. doi:10.1016/j.toxlet.2009.06.120 Workshop 6: Evidence-based Decisions and Toxicovigilance in Human Toxicology W06-01 Overview on evidence based clinical toxicology Hugo Kupferschmidt Swiss Toxicological Information Centre (STIC), Zurich, Switzerland During the last decade, the evidence from scientific research has become an important determinant of clinical decision making, coined as ‘Evidence-based medicine’ (EBM). It has been proposed to translate this concept into toxicology. However, the evidence of causation (important in toxicology, referred to as ‘evidence-based toxicology’) has to be distinguished from the evidence of treatment effects (called ‘evidence-based medicine’ in clinical toxicology). Human studies in toxicology are difficult to perform: volunteer human studies for the testing of toxicity have ethical limitations, and clinical trials to test treatment effects have limitations due to small numbers and the heterogeneity of patients and poisoning circumstances. Recently it has been tried to apply the idea and the methodol- ogy of evidence-based medicine to the field of toxicology, and to review the processes in the scope of hazard, risk, causation and uncertainty. These are important challenges to current regulatory toxicology programmes like REACH. In clinical toxicology there is still little hypothesis-testing research. Randomized clinical trials (RCT) are an exception. Obser- vational studies are often performed on highly selected patient groups thus producing marked bias. In most instances, clinical deci- sions are taken based on expert opinion and guidelines deducted from known pharmacological of toxicological effects, generaliza- tion from substances within the same therapeutic or chemical class, animal data, and case reports. While RCTs will remain rarely applicable, improved and more sophisticated methods of epidemi- ological research in the collection of data on human poisoning are feasible to produce data capable to address the clinical and public health aspect of poisoning. doi:10.1016/j.toxlet.2009.06.109
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Transcript of Mechanistic aspects of in vivo and in vitro testing of allergic agents
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Abstracts / Toxicology L
ocarcinomas in the lungs was observed. The causal role of thenflammatory effects in the chronic pathogeneses developing inhis mouse model and their relevance to human smoking-relatediseases remain to be established.
Acknowledgement: Supported by Philip Morris International andhilip Morris USA.
oi:10.1016/j.toxlet.2009.06.118
05-05echanistic aspects of in vivo and in vitro testing of allergic
gents
hristian Martin
Pharmacology and Toxicology, University Hospital Aachen, Aachen,ermany
wide range of industrial chemicals can induce respiratory allergiceactions. At present, there are no widely applied or fully validatedest methods to identify respiratory allergens, i.e., compounds thatre considered capable of inducing allergic asthma. Hence, theres an urgent need for methods identifying and characterizing theiological action of chemicals in the lung. To discriminate and clas-ify the allergic potential of the different compounds, several inivo and in vitro models were utilized. In order to test rather lowoses of chemicals in vivo, various methods, different applicationoutes, i.e., intradermal, topical or inhalation exposure, differenturation and several species, i.e., guinea pig, rat or mouse weresed. In vivo physiological parameters like respiratory functionalesponse (specific or unspecific), tests in lymph nodes, and cel-ular response in B- and T-cells, macrophages and epithelial cells
ere performed. In addition reliable alternative ex vivo and in vitroethods are to claim. In primary epithelial cells, B- and T-cells,
nd dendritic cells and different cell lines structural cell changes,xpression and release of proteins and mediators (like TH1 andH2 cytokines) were monitored to determine the ability of com-ounds to provoke allergy. As the lung consists of more then 40ifferent cell types, respiratory allergens are hard to define in sin-le cell types. Viable lung slices represent an alternative methodo test functional and immunological responses to chemicalompounds.
Herein, an overview of the different methods and their mech-nistic responses to the industrial chemicals trimellitic anhydrideTMA) and 2,4-dinitrochlorobenzene (DNCB) is given.
oi:10.1016/j.toxlet.2009.06.119
05-06ung fibrosis is uncoupled from inflammation in response tooxic nano- and micro-particles
rancois Huaux ∗, Sandra Lo Re, Marylène Lecocq, Virginie Rabolli,iulia Giordano, Julie Muller, Virginie Barbarin, Dominique Lison
Université catholique de Louvain, Unit of Industrial Toxicology,russels, Belgium
he paradigm that inflammation drives pulmonary fibrosis
as been recently challenged. We observed that nano- andicro-particle-induced lung fibrosis in animals was unpaired tonflammation. The fibrotic disease was also resistant to severalnti-inflammatory therapies and occurred in mice deficient forro-inflammatory cytokines (i.e., IL-1, IL-12p35, IL-17 and type I
ofh
d
189S (2009) S37–S56 S45
FN). Interestingly, silica-induced lung fibrosis in mice was charac-erized by a chronic anti-inflammatory response accompanied by
acrophage-derived anti-inflammatory cytokine overexpressioni.e., IL-10, soluble TNF-� receptors and TGF-�). We showed that IL-0 (like TGF-�) has a detrimental activity during the establishmentf lung fibrosis despite its capacity to control certain macrophageunctions and the inflammatory process. IL-10 deficient or over-xpressing mice developed reduced or enhanced silica-inducedung fibrosis, respectively. The profibrotic activity of IL-10 in vivoppeared to be mediated by its ability to stimulate the expressionf TGF-�1 while suppressing the expression of cyclooxygenase-
and thus production of the anti-fibrotic eicosanoid PGE2.he anti-inflammatory pathway associated with silica-inducedbrotic lesions in mice was not restricted to macrophages since
mmunosuppressive regulatory T cells, estimated by Foxp3 lungxpression, were also accumulated during the development ofung fibrosis. In conclusion, a pronounced anti-inflammatoryeaction may also contribute to particle-induced lung fibrosisnd represent an additional etiopathogenic pathway of lungbrosis.
oi:10.1016/j.toxlet.2009.06.120
orkshop 6: Evidence-based Decisions and Toxicovigilance inuman Toxicology
06-01verview on evidence based clinical toxicology
ugo Kupferschmidt
Swiss Toxicological Information Centre (STIC), Zurich, Switzerland
uring the last decade, the evidence from scientific research hasecome an important determinant of clinical decision making,oined as ‘Evidence-based medicine’ (EBM). It has been proposedo translate this concept into toxicology. However, the evidence ofausation (important in toxicology, referred to as ‘evidence-basedoxicology’) has to be distinguished from the evidence of treatmentffects (called ‘evidence-based medicine’ in clinical toxicology).uman studies in toxicology are difficult to perform: volunteeruman studies for the testing of toxicity have ethical limitations,nd clinical trials to test treatment effects have limitations due tomall numbers and the heterogeneity of patients and poisoningircumstances.
Recently it has been tried to apply the idea and the methodol-gy of evidence-based medicine to the field of toxicology, and toeview the processes in the scope of hazard, risk, causation andncertainty. These are important challenges to current regulatoryoxicology programmes like REACH.
In clinical toxicology there is still little hypothesis-testingesearch. Randomized clinical trials (RCT) are an exception. Obser-ational studies are often performed on highly selected patientroups thus producing marked bias. In most instances, clinical deci-ions are taken based on expert opinion and guidelines deductedrom known pharmacological of toxicological effects, generaliza-ion from substances within the same therapeutic or chemicallass, animal data, and case reports. While RCTs will remain rarelypplicable, improved and more sophisticated methods of epidemi-
logical research in the collection of data on human poisoning areeasible to produce data capable to address the clinical and publicealth aspect of poisoning.oi:10.1016/j.toxlet.2009.06.109
