title: Immune responses induced by diclofenac or carbamazepine in an oral exposure model using TNP-Ficoll as reporter antigen.
abstract: Immune-mediated drug hypersensitivity reactions (IDHR) may result from immuno-sensitization to a drug-induced neo-antigen. They rarely occur in patients and are usually not predicted preclinically using standard toxicity studies. To assess the potential of a drug to induce T-cell sensitization, trinitrophenyl (TNP)-Ficoll was used here as a bystander antigen in animal experiments. TNP-Ficoll will only elicit TNP-specific IgG antibodies in the presence of non-cognate T-cell help. Therefore, the presence of TNP-specific IgG antibodies after co-injection of drug and TNP-Ficoll was indicative of T-cell sensitization potential. This TNP-Ficoll-approach was used here to characterize T-cell help induced by oral exposure to diclofenac (DF) or carbamazepine (CMZ). DF or CMZ was administered orally to BALB/c mice and after 3 w, the mice were challenged in a hind paw with TNP-Ficoll and a dose of the drug that by itself does only elicit a sub-optimal popliteal lymph node assay (PLNA) response. T-cell-dependent responses were then evaluated in paw-draining popliteal lymph nodes (PLN). Also, shortly after oral exposure, mesenteric lymph nodes (MLN) were excised for evaluation of local responses. Both drugs were able to increase PLN cellularity and TNP-specific IgG1production after challenge. Both DF and CMZ stimulated CD4+and CD8+T-cells and caused shifts of the subsets toward an effector phenotype. DF, but not CMZ, appeared to stimulate interferon (IFN)-γ production. Remarkably, depletion of CD8+, but not CD4+, T-cells reduced TNP-specific IgG1production, and was more pronounced in CMZ- than in DF-exposed animals. Local responses in the MLN caused by DF or CMZ also showed shifts of CD4+and CD8+-cells toward a memory phenotype. Together, the data indicate that oral exposure to CMZ and DF differentially induced neo-antigen-specific T-cell reactions in the PLNA.
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.|b TI Pharma, Leiden , The Netherlands.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kwast
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.|c Medicinal Safety Research Laboratories, Daiichi Sankyo Co. Ltd , Tokyo , Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Aida
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.|b TI Pharma, Leiden , The Netherlands.
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Fiechter
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Kruijssen
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.affiliation: d Bioceros , Utrecht , The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.|b TI Pharma, Leiden , The Netherlands.|e Department of Infectious Diseases and Immunology , Utrecht University , Utrecht , The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Ludwig
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences (IRAS), Utrecht University , Utrecht , The Netherlands.
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D002220:Carbamazepine / Q000009:adverse effects* / Q000627:therapeutic use; D004008:Diclofenac / Q000009:adverse effects* / Q000627:therapeutic use; D004342:Drug Hypersensitivity / Q000276:immunology*; D005362:Ficoll / Q000031:analogs & derivatives / Q000276:immunology; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*; D014301:Trinitrobenzenes / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D007074:Immunoglobulin G; C020529:TNP-ficoll; D014301:Trinitrobenzenes; D004008:Diclofenac; D005362:Ficoll; D002220:Carbamazepine; D007371:Interferon-gamma
keywords: Immunotoxicology; T-cells; TNP-Ficoll; immune-dependent drug hypersensitivity reactions; oral administration; reporter antigen