The major goal of this three-year project involving ten academic participants and two biotech companies is to develop novel therapeutic strategies for the treatment of human autoimmune diseases. Therapies in this field still mostly rely on empirical approaches, or on unselected immunosuppression. On one side, patients quite seldom heal. On the other, drugs are responsible for an important part of the morbidity and social costs associated with chronic autoimmunity. They have severe side effects, including potentially life-threatening infective complications. Recently a major advance derived from the observation that a defective clearance of apoptotic cells consistently associates in vivo with autoimmunity. We reason that interventions aimed to enhance the phagocytic ability of the organism may limit the accumulation of apoptotic cells and therefore break the vicious circle that maintains autoimmune responses. We plan to use complementary approaches to gain insight on the molecules that participate to the clearance of apoptotic cells (phagocytic partners). We plan to define their interactions and to identify molecular interventions capable to influence this pathway, bypassing defective events or targeting defined repressor modules. Participants will share technologies and expertise to develop appropriate in vivo models, necessary to dissect a process endowed with many variables (see Section B5.1a). These models will allow the in vivo validation of proposed strategies, aimed to: 1. Prevent tissue accumulation of apoptotic cells. 2. Prevent chronic inflammation and tissue damage. 3. Limit autoimmunity. Secondary objective of this proposal is to exploit the same animal models defective in apoptotic cell clearance (clearance defective animals) to obtain an unbiased source of autoantibodies, which will be used to identify novel autoantigens. A better definition of the intracellular antigens targeted during autoimmune diseases, as well as their association with specific symptoms of the disease or with prognostic trends, would be a valuable addition to the management of autoimmune patients.