Immune reactivity following CD40L blockade: Role in autoimmune glomerulonephritis in susceptible recipients

To investigate the role of costimulation in autoimmune glomerulonephritis t hat develops in the setting of murine chronic graft-vs-host disease (cGVHD) ,we examined the effects of blocking CD40L, a costimulatory marker expresse d on activated CD4(+) T cells, in recipient mice. These studies addressed t he potential role of CD40L blockade in preventing disease and in downregula ting its expression in animals with evidence of autoreactivity, Animals tre ated acutely with anti-CD40L antibody at disease induction do not develop c irculating anti-DNA antibodies, proteinuria, or histologic evidence of rena l disease. If treatment is delayed for two weeks, after circulating anti-DN A antibodies are apparent, all animals develop massive proteinuria by 14 we eks after disease induction, Renal histology of kidneys from the delayed tr eatment and control groups reveal similar glomerular immune deposits, and i ntense staining for CD4, ICAM-1, and I-A(b) in areas of mononuclear cell in filtration, Long-term treatment studies begun two weeks after disease induc tion is not disease-protective, as all animals develop massive proteinuria and renal disease by 14 weeks, These studies suggest that early CD40L signa ling events are critical to induction of allogeneic interactions and autore activity in cGVHD, but that short-term or chronic CD40L blockade, once auto reactivity is evident, does not abrogate systemic autoreactivity and renal involvement.