title: Characterization of the draining lymph node response in the mouse drug allergy model: A model for drug hypersensitivity reactions.
abstract: The mouse drug allergy model (MDAM) was developed as a tool to predict the potential of systemically administered drugs to produce hypersensitivity reactions (HR). Drugs associated with HR in the clinic produce a marked increase in the cellularity of the draining lymph nodes (DLN) in the MDAM. The objective of this study was to characterize the changes in the DLN following exposure to drugs associated with HR and to investigate whether lymphocyte migration and/or proliferation play a role in the response. These endpoints were also investigated in the local lymph node assay (LLNA) to determine whether responses between the two assays occur via similar mechanisms. Results demonstrated that total numbers of T- and B-cells were proportionally increased in the DLN of mice treated with positive control drugs (i.e. abacavir, amoxicillin, ofloxacin, and sulfamethoxazole) compared to animals administered the vehicle or negative control drugs (metformin and cimetidine). In contrast, a significant increase in the B-cell population of the DLN was observed for 2,4-dinitrofluorobenzene (DNFB) following the LLNA protocol. Down-regulation of CD62L and up-regulation of CCR7 were observed for T-cells from the DLN of the positive control treated mice in the MDAM, but not with DNFB in the LLNA. A mild increase in T-cell proliferation was observed in the MDAM with positive control drugs, while DNFB in the LLNA induced proliferation within the B-cell population only. Anti-CD40L antibody administration inhibited MDAM responses to positive control drugs, but did not affect DNFB-induced increases in total cell number in the LLNA. These results suggest that the increased cellularity of the DLN in the MDAM may be the result of drug-induced alterations in lymphocyte migration and/or effects on lymphocyte proliferation. Moreover, it appears that different mechanisms may be involved in driving the MDAM and LLNA responses.
authors.affiliation: Immunotoxicology CoE, Drug Safety Research and Development, Pfizer Inc. , Groton, CT , USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.forename: Susan H
authors.initials: SH
authors.lastname: Cole
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Kawabata
authors.forename: Jessica
authors.initials: J
authors.lastname: Whritenour
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000473:pathology; D005260:Female; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D054400:Receptors, CCR7 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7
keywords: CCR7; CD62L; LLNA; drug hypersensitivity; flow cytometry; lymph nodes; mouse drug allergy model