IL-4 therapy prevents the development of proteinuria in active heymann nephritis by inhibition of tel cells

The role of IL-4, a key Th2 cytokine, in promoting or inhibiting active Hey mann nephritis (HN) was examined. HN is induced by immunization with Fx1A i n CFA, and proteinuria in HN is associated with subepithelial IgG and C3 de position and infiltration of CD8(+) T-cytotoxic I (Tel) cells and macrophag es into glomeruli, as well as induction of Abs to Crry. Treatment with rIL- 4 from the time of Fx1A/CFA immunization stimulated an earlier IgG1 respons e to Fx1A, induced anti-Crry Abs, and up-regulated IL-4 mRNA in lymphoid ti ssue, but did not alter proteinuria. Treatment with MRCOx-81, an IL-4-block ing mAb, resulted in greater proteinuria, which suggests endogenous IL-4 re gulated the autoimmune response. Delay of rIL-4 treatment until 4 wk post-F x1A/ CFA immunization and just before the onset of proteinuria prevented th e development of proteinuria and reduced Tel cell infiltrate in glomeruli. Delayed treatment with IL-4 had no effect on titer or isotype of Abs to Fx1 A or on Ig, C3, and C9 accumulation in glomeruli. Treatment with rIL-13, a cytokine that alters macrophage function such as rIL-4, but has no direct e ffect on T or B cell function, reduced glomerular macrophage infiltrate, bu t did not prevent proteinuria or CD8+ T cell infiltrate. Anti-Crry Abs were paradoxically only induced with rIL-4 therapy, not in HN controls with pro teinuria. It was concluded that the rIL-4 effect was probably by inhibition of Tc1 cells, which normally mediate the glomerular injury that results in proteinuria.