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Mice sensitized with radiation-attenuated Schistosoma mansoni cercariae were treated by a variety of procedures known to interrupt immunoregulatory circuitries in attempts to alter the resistance induced by irradiated cercarial sensitization. Both highly resistant C57BL/6 and the often poorly resistant CBA/J strains were examined. Immunomanipulations included adult thymectomy, or administration of different drugs in relation to the time of challenge infection (day 0). Adult thymectomy was performed 3 weeks prior to sensitization or 3 weeks prior to challenge. Drug treatment included cyclophosphamide given at a dose of 20 mg/kg on alternate days, day -11 through day +11, cimetidine at 50 mg/kg/day, day -7 through day +21, or indomethacin at 2.5 mg/kg/day, day 0 through day +10. In most experiments, irradiated cercarial sensitized C57BL/6 mice developed significant resistance which was not altered by the immunomanipulative regimens used. If however, as fortuitously occurred in two adult thymectomy experiments, irradiated cercarial sensitization did not induce significant resistance, immunomanipulation by adult thymectomy allowed the development of a significant protected state. Similarly, adult thymectomy or cimetidine treatment in concert with immunization of CBA/J mice conferred moderate, statistically significant levels of stable resistance in this normally “less resistant” strain.