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 requ ires T cell costimulatory signals provided in part by T cell surface e xpression of gp39/CD40ligand (CD40L) that engages the B cell receptor CD40 and induces B cell differentiation and immunoglobulin class switc hing. We assessed the effect of disrupting the CD40L-CD40 costimulator y pathway, using a CD40-Ig fusion protein, on the development of membr anous glomerulonephritis (MGN) in the mouse. MGN is induced by mouse a ntibodies that recognize and bind to exogenously administered rabbit a nti-mouse renal tubular brush border (RbAMBB) IgG immobilized in the g lomerular capillary wall. MGN did not occur in nude mice, showing the need of the T cell function. C57Bl/10 mice immunized with RbAMBB and t reated with CD40-Ig fusion protein displayed a delayed autologous resp onse 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 p revent the development of MGN by suppressing T cell-dependent antibody production.