Objetivo . To investigate in both humans and in a defined murine system the effects of mixed exposure to subclinical concentrations of contact irritants. To determine the genetic control of susceptibility to irritants. To describe the role of cytokines, especially TNF-a, in induction of irritant contact dermatitis. To characterize the role of heat shock protein (hsp) 70 and the induction of oxidative stress in the induction and prevention of irritant contact dermatitis reactions. To design an in vitro test to characterize the capacity of irritant compounds to regulate cytokines in keratinocytes, a test that partially will eliminate the need for animal testing.Irritant contact dermatitis affects approximately 2% of the population of the European Union, and in some risk occupations affects up to 15% of workers. Despite its prevalence however little is known about its pathogenesis although pro-inflammatory mediators (cytokines), particularly TNF-a, are thought to play a critical role. Furthermore predictive tests of irritant potential are unreliable and are only capable of examine irritants individually, whereas in many occupations several irritants may exist. This is a matter of considerable importance since there is evidence that irritants may have additive or synergistic effects.Initially, we want to titre in vivo dose/effect relationship of known irritants on the induction of clinical reaction and on cytokine induction, especially TNF-a, and oxidative stress to demonstrate a possible additive effect of irritants following mixed exposures. We want to use these in vivo findings to establish an in vitro screening assay based on the capacity of irritative compounds to induce TNF-a in cultured keratinocytes that partially could eliminate the need for animal testing. Furthermore, we want to demonstrate whether differences in susceptibility towards irritant compounds is controlled at the genetic-level making it possible to identify individuals genetically at increased risk to develop irritant contact dermatitis. One of the major targets for such an involvement is the demonstration of TNF-a polymorphisms. We therefor investigate, both in humans and in defined mouse strains differing only at the TNF-a locus, the correlation between polymorphisms at the TNF-a locus and the capacity to develop irritant reactions following exposure. This could facilitate the identification of risk groups and allow information that aid prevention of this disabling condition of considerable socio-economic impact in Europe. Furthermore, we want to investigate whether cells can be made more resistant towards the harmful effects of irritant compounds by e.g. reducing the capacity of irritants to induce an oxidative stress in the cells and by over-expressing hsp and finally whether this affects the cell in its behavior to secrete inflammatory cytokines. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programa(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Tema(s) 4.5.1 - Dose / effect relationships of agents Convocatoria de propuestas Data not available Régimen de financiación CSC - Cost-sharing contracts Coordinador Københavns Universitet Aportación de la UE Sin datos Dirección 65,Niels Andersens Vej 2900 Køpenhavn Dinamarca Ver en el mapa Coste total Sin datos Participantes (3) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo Istituti Fisioterapici Ospitalieri Italia Aportación de la UE Sin datos Dirección Via San Gallicano 25/A 00153 Roma Ver en el mapa Coste total Sin datos United Medical and Dental Schools of Guy's and St Thomas's Hospitals Reino Unido Aportación de la UE Sin datos Dirección Lambeth Palace Road SE1 7EH London Ver en el mapa Coste total Sin datos WESTFAELISCHE WILHELMS - UNIVERSITAET MUENSTER Alemania Aportación de la UE Sin datos Dirección 56,Von-Esmarschstrasse 56 48149 MUENSTER Ver en el mapa Coste total Sin datos
