title: Oral exposure to drugs with immune-adjuvant potential induces hypersensitivity responses to the reporter antigen TNP-OVA.
abstract: Immune-mediated drug hypersensitivity reactions are important causes of black box warnings and drug withdrawals. Despite the high demand for preclinical screening tools, no validated in vitro or in vivo models are available. In the current study, we used a previously described oral administration model using trinitrophenyl-ovalbumin (TNP-OVA) as an antigen to report immuno-adjuvating effects of the analgesic drug acetaminophen (APAP) and its nonhepatotoxic regioisomer 3'-hydroxyacetanilide (AMAP), the antibiotic ofloxacin (OFLX), the antiepileptic drug carbamazepine (CMZ), and the antidiabetic drug metformin (MET). Furthermore, APAP and AMAP were tested in a popliteal lymph node assay (PLNA) combined with TNP-OVA as reporter antigen (RA). C3H/HeOuJ mice were dosed by oral gavage with diclofenac (DF), APAP, AMAP, OFLX, MET, or CMZ. On the first exposure day, the mice received an ip injection with TNP-OVA. Fifteen days later, they were ear challenged with TNP-OVA and delayed-type hypersensitivity (DTH) responses were assessed 24 h later. One week after challenge, the ear-draining lymph node was removed and TNP-specific antibody-secreting cells were determined. DF, APAP, CMZ, and OFLX showed a significant increase in DTH responses to ear injection with TNP-OVA, whereas AMAP and MET did not. C57BL/6 mice were slightly less responsive to APAP and DF after oral gavage, and importantly both AMAP and APAP were negative in the RA-PLNA. The present work shows that the oral exposure model using RA and the RA-PLNA may serve to screen the immune-adjuvant potential of new chemical entities during preclinical drug development.
authors.affiliation: Division of Toxicology, Institute for Risk Assessment Sciences, Utrecht University, PO Box 80177, 3508 TD Utrecht, The Netherlands.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Kwast
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Fiechter
authors.forename: Ine
authors.initials: I
authors.lastname: Hassing
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Irene S
authors.initials: IS
authors.lastname: Ludwig
authors.forename: Raymond H H
authors.initials: RH
authors.lastname: Pieters
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000083:Acetanilides / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004342:Drug Hypersensitivity / Q000276:immunology*; D005260:Female; D007268:Injections, Epidural; D023441:Local Lymph Node Assay; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015242:Ofloxacin / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D000276:Adjuvants, Immunologic; C038600:trinitrophenyl-ovalbumin; D002220:Carbamazepine; D000082:Acetaminophen; C026137:3-hydroxyacetanilide; D010047:Ovalbumin; D008687:Metformin; D015242:Ofloxacin