IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii.
The role for IL-10 in the immunopathogenesis of acute toxoplasmosis following peroral infection was examined in both genetically susceptible C57BL/6 and resistant BALB/c mice. C57BL/6-background IL-10-targeted mutant (IL-10-/-) mice all died in 2 wk after infection with 20 cysts of the ME49 strain, whereas only 20% of control mice succumbed. Histological studies revealed necrosis in the small and large intestines and livers of infected IL-10-/- mice. The necrosis in the small intestine was the most severe pathologic response and was not observed in control mice. Treatment of infected IL-10-/- mice with either anti-CD4 or anti-IFN-gamma mAb prevented intestinal pathology and significantly prolonged time to death. Treatment of these animals with anti-IL-12 mAb also prevented the pathology. Significantly greater amounts of IFN-gamma mRNA were detected in the lamina propria lymphocytes obtained from the small intestine of infected IL-10-/- mice than those from infected control mice. In common with C57BL/6-background IL-10-/- mice, BALB/c-background IL-10-/- mice all died developing intestinal pathology after infection. Control BALB/c mice all survived even after infection with 100 cysts and did not develop the intestinal lesions. Treatment with anti-IFN-gamma mAb prevented the pathology and prolonged time to death of the infected IL-10-/- mice. These results strongly suggest that IL-10 plays a critical role in down-regulating IFN-gamma production in the small intestine following sublethal peroral infection with Toxoplasma gondii and that this down-regulatory effect of IL-10 is required for prevention of development of IFN-gamma-mediated intestinal pathology and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice.
Suzuki
Y
Y
Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA 94301, USA. ysuzuki@leland.Stanford.edu
Sher
A
A
Yap
G
G
Park
D
D
Neyer
L E
LE
Liesenfeld
O
O
Fort
M
M
Kang
H
H
Gufwoli
E
E
D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000953:Antigens, Protozoan / Q000008:administration & dosage* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000276:immunology; D007411:Intestinal Diseases, Parasitic / Q000235:genetics / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D016019:Survival Analysis; D013997:Time Factors; D014122:Toxoplasma / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000401:mortality* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D015704:CD4 Antigens; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma