title: Oral exposure to immunostimulating drugs results in early changes in innate immune parameters in the spleen.
abstract: The development of immune-dependent drug hypersensitivity reactions (IDHR) is likely to involve activation of the innate immune system to stimulate neo-antigen specific T-cells. Previously it has been shown that, upon oral exposure to several drugs with immune-adjuvant capacity, mice developed T-cell-dependent responses to TNP-OVA. These results were indicative of the adjuvant potential of these drugs. The present study set out to evaluate the nature of this adjuvant potential by focusing on early immune changes in the spleen, by testing several drugs in the same experimental model. Mice were exposed to one or multiple oral doses of previously-tested drugs: the non-steroidal-anti-inflammatory drug (NSAID) diclofenac (DF), the analgesic acetaminophen (APAP), the anti-epileptic drug carbamazepine (CMZ) or the antibiotic ofloxacin (OFLX). Within 24 h after the final dosing, early innate and also adaptive immune parameters in the spleen were examined. In addition, liver tissue was also evaluated for damage. Exposure to APAP resulted in severe liver damage, increased levels of serum alanine aminotransferase (ALT) and local MIP-2 expression. DF exposure did not cause visible liver damage, but did increase liver weight. DF also elicited clear effects on splenic innate and adaptive immune cells, i.e. increased levels of NK cells and memory T-cells. Furthermore, an increase in plasma MIP-2 levels combined with an influx of neutrophils into the spleen was observed. OFLX and CMZ exposure resulted in increased liver weights, MIP-2 expression and up-regulation of co-stimulatory molecules on antigen-presenting cells (APC). The data suggested that multiple immune parameters were altered upon exposure to drugs known to elicit immunosensitization and that broad evaluation of immune changes in straightforward short-term animal models is needed to determine whether a drug may harbor the hazard to induce IDHR. The oral exposure approach as used here may be applied in the future as an immunotoxicological research tool in this type of evaluation.
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, 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, 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, Utrecht University , Utrecht , the Netherlands ;|b TI Pharma , Leiden , the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Kruijssen
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , the Netherlands ;
authors.forename: Rob
authors.initials: R
authors.lastname: Bleumink
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , the Netherlands ;|b TI Pharma , Leiden , the Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Ludwig
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , the Netherlands ;
authors.forename: Marianne
authors.initials: M
authors.lastname: Bol-Schoenmakers
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , the Netherlands ;
authors.forename: Joost
authors.initials: J
authors.lastname: Smit
authors.affiliation: a Division of Toxicology , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , the Netherlands ;
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects; D056704:Adaptive Immunity / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects; D002478:Cells, Cultured; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects; D004342:Drug Hypersensitivity / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D015242:Ofloxacin / Q000008:administration & dosage / Q000009:adverse effects; D013154:Spleen / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D007155:Immunologic Factors; D004008:Diclofenac; D002220:Carbamazepine; D000082:Acetaminophen; D015242:Ofloxacin
keywords: Immunotoxicology; adaptive immunity; drug hypersensitivity; in vivo; innate immunity; oral administration