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Mouse rotavirus (epizootic diarrhea of infant mice) was used as a model to study the role of virus-specific immunity in infection and diarrheal disease. The distribution of viral antigen in intestinal tissues was determined by immunofluorescent staining with anti-simian rotavirus (SA-11) serum. The location and proportion of antigen-positive cells appeared to vary as a function of time postinfection and age of the animal at the time of infection. In animals infected at 1 and 7 days of age, antigen-positive cells (5 to 25%) were first detected (1 day postinfection) in the proximal segment of the small intestine, and infection progressed to the middle and distal segments. At 10 days postinfection, virusinfected cells were no longer observed in the proximal segment. In animals infected at 21 days of age (disease-free), a significantly lower proportion of cells were antigen positive (2 to 5%), and they were restricted to the middle and distal segments of the small intestine. Infection, defined according to the presence of virus and viral antigens in intestinal tissues and by seroconversion in the immunoglobulin M (IgM) isotype as determined by enzyme-linked immunosorbent assay with SA-11 antigen, was observed for all age groups (neonatal to adult), even in the presence of virus-specific serum or intestinal immunoglobulins. On the other hand, diarrheal disease was not detected in neonatal mice (1 to 3 days old) positive for passively acquired virus-specific intestinal IgG. The presence of virus-specific IgA in the intestinal tract at the time of infection did not protect from subsequent diarrheal disease. Virus-specific, cell-mediated immunity, determined by a delayed-type hypersensitivity response, did not develop in neonatal mice infected at 5 and 12 days of age. Reinfection of adult mice was associated with suppression of virus-specific delayed-type hypersensitivity and a significant decrease in the titers of the virus-specific serum IgG and IgA. 917 on July 16, 2020 by guest

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Previous developmental and reproductive toxicity studies conducted in rats with Losartan, a potent AT1 subtype selective angiotensin II receptor antagonist, noted treatment-related effects on the pups of dams treated beyond the second trimester through lactation, as demonstrated by increases in pre- and postweaning pup deaths and decreased pup body weights [Spence et al. (1995) Teratology 51:000-000]. The studies presented here were designed to define the critical period for the induction of neonatal toxicity and to examine the effects of Losartan on kidney development when the drug is administered to the dam beyond the second trimester through lactation. In a developmental toxicity study with postweaning evaluation, pregnant rats were administered 5, 20, and 100 mg Losartan/kg/day on gestation days 6 through 15 (GD 6-15). There were no adverse effects on the F1 generation as assessed by mortality, clinical signs, weight gain, external examinations, developmental signs, behavioral tests, and gross or microscopic examination of the kidney. In a fostering/cross-fostering study, pregnant rats were administered 100 mg Losartan/kg/day on GD 15 through lactation day 20 (LD 20). Following delivery, pups from dams treated with Losartan were fostered to control dams, pups from control dams were fostered to Losartan-treated dams, and pups were also fostered to dams within the same group. Maternal exposure to Losartan during lactation increased the incidence of pup deaths on postnatal days 1-3 (PND 1-3), caused decreased pup weights on PND 7, and decreased performance in the auditory startle test in females and increased performance on the second swim maze test in males, relative to controls. Maternal exposure to Losartan during gestation was associated with decreased pup weight on PND 21 and effects observed on male performance in the swim maze test. Treatment during gestation was also associated with decreased pup cardiac weight as well as drug-induced histopathological changes of the kidneys from F1 pups, including medial hypertrophy of intracortical arterioles and dilatation of the renal pelvis. While the cardiac and renal vascular effects disappeared with time, significant renal lesions were still evident by PND 90. In a late-gestation/lactation study with renal evaluation, pregnant rats were administered 0.5, 1.0, 5.0, 20, and 100 mg Losartan/kg/day on GD 15-LD 20. Maternal toxicity was evident as decreased body weight gain in the 100 mg Losartan/kg/day group.(ABSTRACT TRUNCATED AT 250 WORDS)