Anti-CD40L accelerates renal disease and adenopathy in MRL-lpr mice in parallel with decreased thymocyte apoptosis.
The CD40/CD40L (CD40 ligand) axis regulates several interactions between T cells and B cells. Blocking of CD40 engagement by CD40L inhibits Ig class switch by B cells as well as diminishes T cell response to an immunizing Ag. For these reasons, disruption of CD40/CD40L interactions by anti-CD40L administration or by genetic disruption of CD40L has ameliorated a variety of autoimmune conditions. More recent findings suggest that a direct signal can be transmitted to T cells via their expressed CD40L, which can costimulate proliferation with CD3 or promote germinal center formation. It is therefore possible that treatment with anti-CD40L Ab might produce a different outcome than observed in genetically CD40L-deficient mice. In this regard, we observe that in contrast to the genetic deletion of CD40L in MRL-lpr mice, which diminishes autoimmune disease but has little effect on adenopathy, administration of anti-CD40L to MRL-lpr mice accelerates both of these parameters. This difference appears to result from anti-CD40L actively delivering a signal that inhibits T cell apoptosis in lpr mice. This was confirmed by in vitro studies demonstrating that CD40L cross-linking on lpr thymocytes inhibited apoptosis and surface TCR down-modulation induced by CD3 ligation.
Russell
J Q
JQ
Division of Immunobiology, University of Vermont College of Medicine, Burlington 05405, USA.
Mooney
T
T
Cohen
P L
PL
MacPherson
B
B
Noelle
R J
RJ
Budd
R C
RC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D007274:Injections, Intraperitoneal; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008206:Lymphatic Diseases / Q000209:etiology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand