Abstract
NZB×NZW (NZB/W) F1 mice spontaneously develop an antoimmune disease resembling human systemic lupus erythematosus (SLE). The disease is characterized by the immune. complex-type severe lupus nephritis in association with the production of a variety of antoantibodies, including those to DNA. As the production of IgG anti-DNA antibodies in these mice is highly dependent on helper T cells and is strictly restricted by the major histocompatibiliy complex (MHC) heterozygosity of H-2d from NZB and H-2Z from NZW mice, the interplay between F1-unique mixed haplotype MHC class II molecules on B cells and a certain repertoire of T cell receptor may play an important role in this process.
In the present studies, we treated NZB/W F1 mice with anti-MHC class II monoclonal antibodies (anti-I-E) for about 2 months before the onset of disease and examined the effect on the disease severity. The results demonstrated that anti-I-E treatment markedly prolonged the survival and reduced the severity of disease. The serum levels of anti-DNA antibodies were significantly decreased in the treated mice. The possible mechanisms of the effects were suggested by studies on a cellular basis. A notable finding on the B cells was the preferential reduction in the number of the CD5+ B1 cell subset which is known to be responsible for autoantibody production. Although the number of this B cell subset recovered gradually, the serum levels of anti-DNA antibodies, particularly of IgG class, did not reach the levels in the control, untreated mice. Together with the finding that the treatment prevented the generation of activated CD4+ cells in the blood, which normally increase with aging in untreated NZB/W F1 mice, these findings suggested that either central or peripheral self tolerance is at least partly induced in these mice by the treatment. Clarification of this mechanism may contribute to the future application of anti-HLA class II monoclonals for the therapy of human SLE.
