Effects of intranasal administration of cholera toxin (or Escherichia coli heat-labile enterotoxin) B subunits supplemented with a trace amount of the holotoxin on the brain

Effects of intranasal administration of cholera toxin (CT) [or Escherichia coli heat-labile enterotoxin (LT)] B subunits supplemented with a trace amount of the holotoxin. CTB* or LTB*, on the brain were examined in BALB/c mice by comparing with those of the intracerebral injection. Intracerebral injection of CTB* at doses more than 10 mug/mouse caused significant body weight loss and dose-dependent death within 7 days, with localization of conjugates of horseradish peroxidase with CTB (HRP-CTB) in the ventricular system and in the perineural space of olfactory nerves of the nasal mucosa 3 h after injection. Intracerebral injection of CTB* at doses less than 3 mug/mouse (or LTB* at doses less than 27.7 mug/mouse) did not cause any significant body weight loss for 7 days, with localization of HRP-CTB in the brain but not in the nasal mucosa. On the other hand, intranasal administration of 10 mug of CTB* caused localization of HRP-CTB in the nasal mucosa but not in the brain 3 h after administration and caused body weight loss even after 30 administrations. Neither any histological changes of blain tissues nor marl;ed changes in serum biochemical parameters were found in mice after the 30 administrations of CTB* or LTB*. These results suggest that 0.1 mug of CTB* or LTB*, which is known to be close to the minimal effective dose as an adjuvant for nasal influenza vaccine in mice and corresponds to 100 mug per person, can be used as a safe nasal adjuvant without adversely affecting the brain. (C) 2001 Elsevier Science Ltd. All rights reserved.