The TOLERATE training network offers a highly innovative research programme focused on the orphan autoimmune disease iTTP.
TOLERATE focuses on the orphan disease iTTP, an autoimmune disease caused by autoantibodies against only one self-antigen ADAMTS13 (A Disintegrin and Metalloprotease with ThrombSspondin Type 1 repeats, number 13). ADAMTS13 consists of a metalloprotease, a disintegrin-like, a first thrombospondin type 1 repeat (T), a cysteine-rich (C) and a spacer (S) domain, 7 additional T domains and 2 CUB domains. When ADAMTS13 is deficient, hyper-reactive ultra-large von Willebrand factor (VWF) multimers accumulate in the circulation and spontaneously interact with platelets, forming aggregates that block micro-capillaries and deprives organs from oxygen supply. As a consequence, patients develop severe thrombocytopenia, haemolytic anemia and organ failure. The mortality rate is high (>90%) when patients are not diagnosed correctly and treated immediately.
Microaggregates block capillaries in acquired TTP patients. UL-VWF (black) is secreted by endothelial cells. Due to the presence of anti-ADAMTS13 autoantibodies, ADAMTS13 (green scissors) is unable to digest the UL-VWF multimers. UL-VWF hence spontaneously bind platelets forming microaggregates.
Developing novel immune therapies for iTTP paves the way for development of immune therapies for more complex autoimmune diseases where multiple self-antigens play a role. In addition, iTTP is a rare disease allowing a faster route to the market of novel therapies given the orphan designation status that can be applied for with the EMA.
The TOLERATE research plan has been organised in to five scientific work-packages (WP)
WP1 aims at developing innovative T cell therapies: UniCAR-T cell therapy, RevCAR-T cell therapy and TCR-engineered Treg therapy, for autoimmune diseases using iTTP as a model disease.
WP1 is led by Prof. Karen Vanhoorelbeke (KUL).
WP2 objective is to develop tolerogenic vaccines for iTTP and test these in vitro and in vivo in a mouse model of iTTP and to generate liposome-based nanoparticles in order to arrest autoimmunity in vitro and in a mouse model for iTTP.
WP2 is led by Prof. Jan Voorberg (SNQ).
WP3 will define the biological mechanisms involved in ADAMTS13 clearance and promote tolerance by retargeting ADAMTS13 to specific clearance pathways in antigen presenting cells.
WP3 is led by Prof. James O’Donnell (RCSI).
WP4 aims at developing and using standardised medical databases and biobanks for long-term follow-up of autoimmune diseases to better understand the pathophysiology and optimize treatment.
WP4 is led by Prof. Zoltán Prohászka (SMW).
WP5 will capitalize on the results from WP1-4 in order to identify the most promising (combined) innovative therapy.
WP5 is led by Prof. Paul Coppo and Agnes Veyradier (AP-HP).