title: Development of an oral exposure mouse model to predict drug-induced hypersensitivity reactions by using reporter antigens.
abstract: The capability of certain drugs to cause immune-mediated drug hypersensitivity reactions in susceptible individuals has initiated a search for pre-clinical screening tools to identify immunosensitizing drugs. Since most drugs are taken orally, hazard assessment of their immunosensitizing potential should include oral exposure models. In this study, the predictive value of the reporter antigen (RA) approach was investigated in combination with oral or intraperitoneal (ip) exposure to a selection of allergenic drugs, i.e., D-penicillamine (D-Pen), Diclofenac (DF), or Nevirapine (Nevi). The RA trinitrophenyl-Ovalbumin (TNP-OVA) was used to assess the capacity of the drugs to stimulate systemic immune responses to a bystander antigen, whereas the RA TNP-Ficoll was used to indicate whether the drugs were able to induce specific anamnestic T-cell responses. TNP-OVA was injected (ip) in C3H/HeOuJ mice that were subsequently exposed (orally or ip) to one of the drugs via different exposure protocols. All three model drugs used resulted in delayed type hypersensitivity reactions to TNP-OVA after ip and oral exposure. In addition, TNP-specific serum antibody levels were increased after ip exposure to Nevi, and after both oral and ip exposure to D-Pen and DF. These data indicate that the present drugs are able to stimulate immune responses to bystander antigens. Responses to TNP-Ficoll were measured in the popliteal lymph node of BALB/c mice three weeks after they received a single oral dose of D-Pen or DF. Results of this approach show that orally pre-treated mice responded with enhanced responses (TNP-specific IgG1 and IFN-gamma production) to sub-optimal doses of D-Pen or DF in a drug-specific manner. Data with TNP-Ficoll indicate that these drugs stimulate systemic formation of specific T cells. Together, the RA-approach allows assessment of systemic sensitization upon oral and/or ip exposure to the selected drugs. To further evaluate the utility of these models, more drugs, including non-allergenic drugs and those that require metabolic conversion to become allergenic need to be studied in the present models.
authors.affiliation: Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, Utrecht, The Netherlands. s.nierkens@iras.uu.nl
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Marloes
authors.initials: M
authors.lastname: Aalbers
authors.forename: Marianne
authors.initials: M
authors.lastname: Bol
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.forename: Ine
authors.initials: I
authors.lastname: Hassing
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000284:Administration, Oral; D000485:Allergens / Q000008:administration & dosage / Q000145:classification / Q000633:toxicity*; D000818:Animals; D000937:Antigen-Antibody Reactions / Q000187:drug effects*; D000941:Antigens / Q000494:pharmacology*; D004195:Disease Models, Animal; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000473:pathology; D005260:Female; D005362:Ficoll; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007274:Injections, Intraperitoneal; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010047:Ovalbumin / Q000276:immunology; D011237:Predictive Value of Tests
chemical_list: D000485:Allergens; D000941:Antigens; D005362:Ficoll; D010047:Ovalbumin