Interferon-gamma is required during the initiation of an organ-specific autoimmune disease.
Autoimmune gastritis induced by neonatal thymectomy of mice is a CD4+ T cell-mediated organ-specific autoimmune disease. The characteristic features of autoimmune gastritis, which include a mononuclear infiltrate within the gastric mucosa, loss of parietal and chief cells and circulating autoantibodies to the gastric H+/K+ ATPase, appear 6-10 weeks after thymectomy. Here we have assessed the role of interferon-gamma (IFN-gamma) in the pathogenesis of the gastric lesion. Splenic T cells derived from mice with gastritis produced three- to tenfold more IFN-gamma than T cells from normal animals after stimulation with anti-CD3 antibodies. Treatment of neonatally thymectomized mice at weekly intervals for 6 or 12 weeks with a neutralizing rat monoclonal antibody to mouse IFN-gamma abolished the production of anti-gastric autoantibodies and decreased the incidence of gastric mononuclear infiltrates from the 69% observed in normal rat immunoglobulin (Ig)-injected mice to 16%. Further, in mice treated with only a single dose of anti-IFN-gamma immediately after thymectomy at 3 days after birth, the incidence of autoimmune gastritis was 1/19 compared to 8/19 in normal rat Ig-injected mice. Prevention of autoimmunity by neutralization of IFN-gamma several weeks prior to the detection of a pathological lesion strongly suggests that IFN-gamma plays an essential role in the initiation of the gastric autoimmune response.
Barrett
S P
SP
Department of Pathology and Immunology, Monash University Medical School, Melbourne, Australia.
Gleeson
P A
PA
de Silva
H
H
Toh
B H
BH
van Driel
I R
IR
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000209:etiology* / Q000517:prevention & control; D004306:Dose-Response Relationship, Immunologic; D005756:Gastritis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013934:Thymectomy
D000911:Antibodies, Monoclonal; D007371:Interferon-gamma