How Does blockade of CD40/CD40L Prevent Autoimmunity?

DESCRIPTION (provided by applicant): All three projects of the consortium
application are targeted at better understanding induction of long-term
tolerance by costimulation blockade of CD40/CD40L interactions with aCD40L
antibody. We believe that this immune-based intervention is one of the most
promising and attractive approaches currently in clinical trials for several
autoimmune disorders. Many of these ongoing interventions (psoriasis,
transplantation etc.) show much promise and only one trial had to be stopped
due to deleterious side effects (enhanced blood clotting), which was likely
caused by the antibody preparation or too high dosages, since it did not occur
in other clinical studies. Although it is known that CD40-CD40L interactions
are required for dendritic cell maturation and activation, as well as
generation of effector lymphocytes, many mechanistic issues remain unresolved.
The most crucial of these will be tackled by the three projects united in the
present U-19. Effects on lymphocyte differentiation and effector functions
(Sarvetnick), T cell proliferation, differentiation and APC-trafficking
(Miller) and induction of regulatory APCs or lymphocytes able to down-modulate
aggressive autoimmune responses antigen specifically (von Herrath) will be
studied by the single components. In addition to analyzing differential
effector mechanisms, three distinct models for autoimmune diseases will be
utilized (Sarvetnick, NOD; Miller, EAE; von Herrath, RIP-LCMV). This multi-focal
approach will result in a more rapid and thorough understanding of a
CD40L induced immune modulation and/or suppression. Furthermore, paradigms or
discoveries applicable to a human situation should ideally be validated and
tested in various animal models. Therefore, the direct comparison of three
autoimmune models will enable us to define, which in vivo consequences of
costimulation blockade occur more commonly and which are restricted to a given
experimental situation.