Immune reactivity following CD40L blockade: role in autoimmune glomerulonephritis in susceptible recipients.
To investigate the role of costimulation in autoimmune glomerulonephritis that develops in the setting of murine chronic graft-vs-host disease (cGVHD), we examined the effects of blocking CD40L, a costimulatory marker expressed on activated CD4+ T cells, in recipient mice. These studies addressed the potential role of CD40L blockade in preventing disease and in downregulating its expression in animals with evidence of autoreactivity. Animals treated acutely with anti-CD40L antibody at disease induction do not develop circulating anti-DNA antibodies, proteinuria, or histologic evidence of renal disease. If treatment is delayed for two weeks, after circulating anti-DNA antibodies are apparent, all animals develop massive proteinuria by 14 weeks after disease induction. Renal histology of kidneys from the delayed treatment and control groups reveal similar glomerular immune deposits, and intense staining for CD4, ICAM-1, and I-A(b) in areas of mononuclear cell infiltration. Long-term treatment studies begun two weeks after disease induction is not disease-protective, as all animals develop massive proteinuria and renal disease by 14 weeks. These studies suggest that early CD40L signaling events are critical to induction of allogeneic interactions and autoreactivity in cGVHD, but that short-term or chronic CD40L blockade, once autoreactivity is evident, does not abrogate systemic autoreactivity and renal involvement.
Banu
N
N
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Zhang
Y
Y
Meyers
C M
CM
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000276:immunology / Q000662:veterinary*; D006086:Graft vs Host Disease / Q000276:immunology / Q000662:veterinary*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007668:Kidney / Q000473:pathology*; D051379:Mice; D008811:Mice, Inbred DBA; D011507:Proteinuria / Q000652:urine / Q000662:veterinary
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D018799:Intercellular Adhesion Molecule-1