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.
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