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 characteristi c features of autoimmune gastritis, which include a mononuclear infilt rate within the gastric mucosa, loss of parietal and chief cells and c irculating autoantibodies to the gastric H+/K+ ATPase, appear 6-10 wee ks after thymectomy. Here we have assessed the role of interferon-gamm a (IFN-gamma) in the pathogenesis of the gastric lesion. Splenic T cel ls derived from mice with gastritis produced three- to tenfold more IF N-gamma than T cells from normal animals after stimulation with anti-C D3 antibodies. Treatment of neonatally thymectomized mice at weekly in tervals for 6 or 12 weeks with a neutralizing rat monoclonal antibody to mouse IFN-gamma abolished the production of anti-gastric autoantibo dies and decreased the incidence of gastric mononuclear infiltrates fr om the 69 % observed in normal rat immunoglobulin (Ig)-injected mice t o 16 %. Further, in mice treated with only a single dose of anti-IFN-g amma immediately after thymectomy at 3 days after birth, the incidence of autoimmune gastritis was 1/19 compared to 8/19 in normal rat Ig-in jected mice. Prevention of autoimmunity by neutralization of IFN-gamma several weeks prior to the detection of a pathological lesion strongl y suggests that IFN-gamma plays an essential role in the initiation of the gastric autoimmune response.