Inhibition of the CD40-CD40ligand pathway prevents murine membranous glomerulonephritis.
Several forms of glomerulonephritis are induced by antibodies against self or foreign antigens. Normal B lymphocyte antibody production requires T cell costimulatory signals provided in part by T cell surface expression of gp39/CD40ligand (CD40L) that engages the B cell receptor CD40 and induces B cell differentiation and immunoglobulin class switching. We assessed the effect of disrupting the CD40L-CD40 costimulatory pathway, using a CD40-Ig fusion protein, on the development of membranous glomerulonephritis (MGN) in the mouse. MGN is induced by mouse antibodies that recognize and bind to exogenously administered rabbit anti-mouse renal tubular brush border (RbAMBB) IgG immobilized in the glomerular capillary wall. MGN did not occur in nude mice, showing the need of the T cell function. C57Bl/10 mice immunized with RbAMBB and treated with CD40-Ig fusion protein displayed a delayed autologous response and absence of MGN lesions, while control fusion proteins failed to prevent the development of the disease. These observations provide evidence that disruption of the CD40-CD40L costimulatory pathway can prevent the development of MGN by suppressing T cell-dependent antibody production.
Biancone
L
L
Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, USA.
Andres
G
G
Ahn
H
H
DeMartino
C
C
Stamenkovic
I
I
D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015433:Glomerulonephritis, Membranous / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007136:Immunoglobulins / Q000235:genetics; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012995:Solubility
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007136:Immunoglobulins; D008024:Ligands; D015335:Molecular Probes; D011993:Recombinant Fusion Proteins