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 betwe en 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 interactio ns by anti-CD40L administration or by genetic disruption of CD40L has ameliorated a variety of autoimmune conditions. More recent findings s uggest that a direct signal can be transmitted to T cells via their ex pressed CD40L, which can costimulate proliferation with CD3 or promote germinal center formation. It is therefore possible that treatment wi th anti-CD40L Ab might produce a different outcome than observed in ge netically CD40L-deficient mice. In this regard, we observe that in con trast to the genetic deletion of CD40L in MRL-lpr mice, which diminish es autoimmune disease but has little effect on adenopathy, administrat ion of anti-CD40L to MRL-lpr mice accelerates both of these parameters . This difference appears to result from anti-CD40L actively deliverin g a signal that inhibits T cell apoptosis in lpr mice. This was confir med by in vitro studies demonstrating that CD40L cross-linking on lpr thymocytes inhibited apoptosis and surface TCR down-modulation induced by CD3 ligation.