title: IL-10 is not required to prevent immune hyperactivity during memory responses to Toxoplasma gondii.
abstract: Primary infection of IL-10 knockout (KO) mice with the protozoan parasite Toxoplasma gondii leads to a CD4(+)-T-cell dependent shock-like reaction with high systemic levels of IL-12 and IFN-gamma, severe liver pathology and death of mice. In the present study, this immune-mediated pathology was prevented by treatment of IL-10 KO mice with the anti-parasitic drug sulfadiazine, allowing these mice to progress to the chronic phase of infection. To address the role of endogenous IL-10 in the regulation of secondary immune responses to T. gondii, IL-10 KO mice were infected with the avirulent Me49 strain of this parasite, treated with sulfadiazine for 2 weeks starting at day 3 p.i., and were rechallenged 6 weeks p.i. with RH, a highly virulent strain of T. gondii. In these studies, chronically infected IL-10 KO mice survived secondary infection with RH and controlled parasite load. Although serum levels of IL-12 and IFN-gamma were higher in IL-10 KO mice than in wild type (WT) mice 8 days after RH rechallenge, these levels were well controlled in the absence of endogenous IL-10, suggesting that IL-10 is not required to down-regulate cytokine production during the memory response. Antigen-specific ex vivo recall responses further revealed that splenocytes from chronically infected WT and IL-10 KO mice responded to parasite antigen with similar production of IL-12 and IFN-gamma, and there was also no significant difference in ex vivo production of these cytokines by splenocytes in response to parasite antigen 7 days after secondary infection with T. gondii. Furthermore, IL-10 KO mice immunized with the Ts-4 vaccine-strain of T. gondii were protected when rechallenged with the virulent RH strain. Together, these studies demonstrate that the inhibitory effect of IL-10, which is required to prevent immune-mediated pathology during primary infection, is not required to prevent immune hyperactivity during a secondary response to T. gondii, and a highly effective memory response is generated in the absence of endogenous IL-10.
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. uwille@mail.nih.gov
authors.forename: U
authors.initials: U
authors.lastname: Wille
authors.forename: M
authors.initials: M
authors.lastname: Nishi
authors.forename: L
authors.initials: L
authors.lastname: Lieberman
authors.forename: E H
authors.initials: EH
authors.lastname: Wilson
authors.forename: D S
authors.initials: DS
authors.lastname: Roos
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use; D001921:Brain / Q000469:parasitology; D005260:Female; D006651:Histocytochemistry; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D053762:Interleukin-12 Subunit p40; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000469:parasitology; D021122:Protein Subunits / Q000276:immunology; D018709:Statistics, Nonparametric; D013411:Sulfadiazine / Q000627:therapeutic use; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
chemical_list: D000981:Antiprotozoal Agents; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D013411:Sulfadiazine; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma