CONSTITUTIVE EXPRESSION OF INTERLEUKIN (IL)-4 IN-VIVO CAUSES AUTOIMMUNE-TYPE DISORDERS IN MICE

The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surfa ce MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels. Tg mice develop anemia, glomerulonephriti s with complement and immune deposition in the glomeruli, and show inc reased production of autoantibodies. Treatment of IL,-4 tg mice with a nti-IL-4 neutralizing antibodies protected the mice from disease devel opment, showing that IL-4 was responsible for the observed disorders. Deletion of superantigen responsive autoreactive T cells in the IL-4 t g mice was normal and treatment of mutant mice with deleting anti-CD4 antibodies failed to ablate the onset of autoimmune-like disease, sugg esting that CD4(+) T cells were not the primary cause of the disorders . Furthermore, the deletion of B cells reacting against MHC class I mo lecules was also normal in the IL-4 tg mice. Therefore the most likely explanation for the increased production of autoantibodies and the au toimmune-like disorders is that IL-4 acts directly on autoreactive B c ells by expanding them in a polyclonal manner. Taken together our resu lts show that inappropriate multi-organ expression of IL-4 in vivo lea ds to autoimmune-type disease in mice.