T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.

Objective: Licarbazepine is being developed for the treatment of bipolar disorder. This study investigated its dose proportional pharmacokinetics and safety in healthy subjects. Methods: In an open‐label, randomized, three‐treatment, three‐period, three‐sequence crossover study, 13 healthy men and women (18‐50 years of age; 2 discontinued and one was replaced) were administered 250, 500, or 1000 mg of licarbazepine orally as a single dose followed by twice daily (bid) administrations for 4.5 days, under fasted conditions. Results: Single‐dose licarbazepine pharmacokinetics were slightly over‐proportional with respect to area under the curve (AUC∞), but were dose proportional for maximum plasma concentration (Cmax). Multiple‐dose licarbazepine pharmacokinetics were proportional across the dose range for steady‐state AUCτ,Cmax, and Cmin. The time to Cmax (1–2 hours) and elimination half‐life (7.6–9.2 hours) were dose independent and did not change substantially with multiple dosing. Steady state was reached after 3 days of bid dosing, and licarbazepine accumulation was approximately 2.5 for all doses. Single and multiple oral doses of 250‐ and 500‐mg licarbazepine were safe and well tolerated; 1000‐mg doses were associated with more adverse events. Conclusions: The favorable pharmacokinetic characteristics of licarbazepine suggest that it may be an easy‐to‐use treatment option for bipolar disorder.