T Cell‐dependent B‐Cell Proliferation and Activation Induced by Administration of the Drug Diphenylhydantoin to Mice

We have postulated that binding of the hydrophobic anticonvulsant drug diphenylhydantoin (DPH) to lymphoid cells might induce graft-versus-host (GVH)-like cell reactions by T lymphocytes and thus trigger autoimmunization and lymphoma development observed in patients treated with DPH. This hypothesis was studied in mice by means of the popliteal lymph node (PLN) assay. DPH, injected s.c. into the footpads of mice, induced a significant T cell-dependent PLN enlargement. The B cell-derived population comprised the majority of cells in the enlarged PLN. A T cell-dependent activation of Ig-secreting cells in the PLN was induced by DPH. Thymectomy of young adult mice significantly amplified the PLN reaction to DPH and facilitated the activation of Ig-secreting cells. Since injection of the hydantoin rings only completely failed to induce PLN reactions, it is assumed that the observed PLN reactions are caused by the phenyl groups and/or the highly reactive intermediates of DPH. In conclusion, DPH can induce a T cell-dependent proliferation and functional activation of B cells. Conceivably, if such a process persists, it might lead to the GVH-like lymphomagenesis and autoimmunization observed in patients treated with this drug.