GENETIC-CONTROL OF ACQUIRED-RESISTANCE TO HELIGMOSOMOIDES-POLYGYRUS -OVERCOMING GENETICALLY-DETERMINED WEAK RESPONDER STATUS BY STRATEGIC IMMUNIZATION WITH IVERMECTIN-ABBREVIATED INFECTIONS

The induction of acquired resistance to H. polygyrus, following treatm ent of mice by a 6 day immunizing infection abbreviated with the anthe lmintic drug ivermectin (6d I-AI), was investigated. Four worms were s ufficient to elicit >80% protection against challenge and immunizing i nfections >50 worms generated >95% protection in female NIH mice. A fe w worms were recovered during the second week from immunized challenge d mice but these were rapidly expelled from the gut lumen. Treatment w ith hydrocortisone from day 10 postinfection, permitted worm burdens t o accumulate over the following 2 weeks. The 6d I-AI protocol enabled females of strains previously designated as weak responders to develop potent acquired resistance to challenge (CBA mice showed >90% protect ion), although weak responder strain male mice were not significantly protected. Delaying treatment with ivermectin by as little as 24 h res ulted in poorer expression of acquired resistance. A positive correlat ion between the increasing interval from infection to treatment with i vermectin and worm burdens after challenge, and the negative correlati on with IgG1 antibody responses after challenge indicated that the imm unodepressive activities of 7 day and older worms down-regulated local intestinal immune responses. Mice characterized by weak responder phe notype were significantly more sensitive to downregulation than mouse strains showing strong responder phenotype. Ln consequence, optimal ti ming of treatment with anthelmintics during exposure to the immunizing infection, intending to minimize exposure to the immunodepressive sta ges of the parasite, is sufficient to overcome reported genetic constr aints on the development of resistance in this system.