title: Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS.
abstract: The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.
authors.affiliation: Centre for the Study of Host Resistance, Montreal General Hospital Research Institute, Quebec, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Stevenson
authors.forename: M F
authors.initials: MF
authors.lastname: Tam
authors.forename: M
authors.initials: M
authors.lastname: Belosevic
authors.forename: P H
authors.initials: PH
authors.lastname: van der Meide
authors.forename: J E
authors.initials: JE
authors.lastname: Podoba
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007109:Immunity; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010961:Plasmodium / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins; D013154:Spleen / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D007371:Interferon-gamma