title: Long-term treatment with 5,5-diphenylhydantoin reduces lymphadenopathy and anti-ssDNA autoantibodies in C57BL/6-lpr/lpr mice.
abstract: To further the insight in the immunomodulating properties of the anticonvulsant 5,5-diphenylhydantoin (DPH), C57BL/6 (B6), C57BL/6-lpr/lpr (B6-lpr/lpr) and MRL/MpJ- +/+ (MRL) mice received DPH orally for six months to determine weekly urinary biopterin levels, a potential T-cell activation marker, by high performance liquid chromatography. At the end of the experiment serum antibody levels were measured by ELISA and relative lymphoid organ weights determined. DPH treatment resulted in reduced body weight in all strains, reduced spleen weights in B6 and MRL mice, profoundly reduced popliteal lymph node weights in B6-lpr/lpr mice and increased thymus weights in MRL mice. DPH treatment decreased serum IgM, IgG and IgA as well as IgM and IgG anti-ssDNA levels in B6-lpr/lpr mice, but did not affect these parameters in other strains. Effects of DPH on IgM rheumatoid factor levels in B6-lpr/lpr mice were inconsistent. Urinary biopterin levels of untreated B6 and B6-lpr/lpr mice were about equal and lower than those of MRL mice. During the first three months of DPH treatment, persistently elevated biopterin levels were observed in B6 and to a lesser degree in MRL mice, and alternately elevated and control levels in B6-lpr/lpr mice. Thereafter, the effects faded in all strains. Results show that long-term DPH treatment causes only minor lymphoid organ weight changes in B6 and MRL mice, but causes a clear reduction of the lymphadenopathy and (auto)antibody formation in B6-lpr/lpr mice. Observed changes could not be related to altered biopterin excretion indicating that the latter is an inappropriate marker of murine autoimmune disease.
authors.affiliation: Research Institute of Toxicology, Utrecht University, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Bloksma
authors.forename: J M
authors.initials: JM
authors.lastname: de Bakker
authors.forename: H J
authors.initials: HJ
authors.lastname: van Rooijen
authors.forename: P
authors.initials: P
authors.lastname: Punt
authors.forename: W
authors.initials: W
authors.lastname: Seinen
authors.forename: M E
authors.initials: ME
authors.lastname: Kammüller
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D001708:Biopterins / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008206:Lymphatic Diseases / Q000188:drug therapy* / Q000276:immunology; D008221:Lymphoid Tissue / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D010672:Phenytoin / Q000008:administration & dosage / Q000494:pharmacology*; D012217:Rheumatoid Factor / Q000187:drug effects
chemical_list: D000974:Antibodies, Antinuclear; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D001708:Biopterins; D010672:Phenytoin; D012217:Rheumatoid Factor