TOLERATE Research
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.