A superagonistic monoclonal antibody for CD28 ameliorates crescentic glomerulonephritis in wistar-kyoto rats

Abstract

Regulatory T (Treg) cells play an important role in the resolution of crescentic glomerulonephritis, where a T helper 1 (Th1)-predominant immune response promotes crescent formation. Therefore, agents that increase Treg cells appear to be ideal for suppressing T-cell-mediated renal pathology. We hypothesized that a superagonistic monoclonal antibody for CD28 (JJ316), which has been known to preferentially expand Treg cells in vivo, could prevent nephrotoxic serum-induced nephritis in Wistar-Kyoto rats, one of the experimental models of crescentic glomerulonephritis. Administration of JJ316 attenuated crescent formation, proteinuria and glomerular accumulation of macrophages and CD8(+) T cells. These changes were accompanied by increased infiltration of Treg cells. Among glomerular macrophages, the CD163(+) subset was significantly increased after treatment, suggesting that Treg cells may modulate the phenotype of macrophages leading to resolution of glomerulonephritis. In an adoptive transfer experiment, two T-cell subsets (CD4(+)CD25(+) and CD4(+)CD25(-) T cells) purified from spleens and lymph nodes of donor rats primed with JJ316 3 d before were inoculated into nephritic recipient rats, which recapitulated the beneficial effects of in vivo administration of JJ316. Furthermore, a single injection of JJ316 administered 3 d after disease induction completely protected nephritic rats from death for 2 months. In conclusion, we demonstrated that treatment with JJ316 has a dramatic therapeutic effect on an experimental crescentic glomerulonephritis, possibly due to expansion and activation of Treg cells.