None of three, however, regained kidney function enough to stop dialysis

None of three, however, regained kidney function enough to stop dialysis. of autoimmunity, and treatment with IdeS has successfully been used to inactivate HLA alloantibodies in patients undergoing renal transplantation. Both IdeS and EndoS have the potential Topiroxostat (FYX 051) to become precision tools to replace plasmapheresis in the treatment of vasculitic emergencies and a clinical trial of IdeS in anti-GBM vasculitis is now ongoing. Keywords: vasculitis, ANCA, studies indicate a role for anti-neutrophil cytoplasm antibodies (ANCA) in the pathogenesis of small vessel vasculitides such as microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) (16, 17). There are many ANCA specificities in different autoimmune diseases but only myeloperoxidase (MPO) and proteinase 3 (PR3) that are expressed on the surface of primed neutrophils are major ANCA-antigens in vasculitis (8). The most compelling evidence for a role of ANCA in the pathogenesis comes from animal models of MPO-ANCA, where antibodies alone or antibody producing cells can transfer the disease (18). However, there are also data that do not support a direct role for ANCA in the pathogenesis; all purified IgG preparations from patients do not active neutrophils in a consistent manner (19, 20). IgA vasculitis (21) and cryoglobulinemic vasculitis (22) are immune complex mediated diseases, where polyclonal or monoclonal autoantibodies react with other immunoglobulins to form complexes. In Topiroxostat (FYX 051) urticarial vasculitis there are often autoantibodies directed to the complement factor C1q, which also lead to immune complex formation (23). Immune complexes activate complement primarily through the classical pathway which results in neutrophil influx and vessel wall damage (23). Physiochemical properties such as size and temperature determine where and when they will deposit, in urticarial vasculitis the direct targeting of the complement system also affect symptoms and signs. IdeS and EndoS infects only humans, and from an evolutionary point of view it is noteworthy that the cleavage of IgG in other species is more restricted; in mice for instance subclasses 2a/c and 3 are sensitive, but not 1 and 2b (26). Human IgG contains one N-linked glycan attached to Asn237 on the heavy chain (27). It is of great importance for effector functions such as complement activation and neutrophil recruitment. There are several bacterial enzymes that modifies N-linked glycans, but the first IgG specific glycan hydrolase to be described was EndoS which is also produced (28). EndoS cleaves most of the carbohydrate moiety from IgG but leaves an N-acetylglucosamine with an alpha-linked fucose on protein backbone. EndoS treatment leads to reduced complement activation and phagocytosis of bacteria. IdeS and EndoS in Experimental Models The species specificity hampers to use of IdeS in many rodent models. Not surprising is that pretreatment of pathogenic autoantibodies with IdeS can abolish disease in passive transfer models, such as immune thrombocytopenic purpura, neuromyelitis optica, and collagen induced arthritis (26, 29). What is more encouraging is that is that mice can be rescued from a lethal dose of rabbit anti-mouse thrombocytes and that arthritis induced by mouse IgG2a antibodies can be reduced in severity by IdeS (26). EndoS is easier to employ in experimental rodent models and have been shown to be effective to prevent or to treat disease in multiple settings, also in strains that spontaneously develop systemic inflammation (30). The effect of IdeS and EndoS has also been investigated in experimental models of vasculitis. A mouse/rabbit model had been developed to mimic essential steps in the pathogenesis of anti-GBM disease. Here we took advantage of IgG species differences. Mice are first given a bolus dose of rabbit anti-mouse IgG; since rabbit IgG Topiroxostat (FYX 051) cannot activate mouse complement (31) this has no consequences. A week later, when there is no longer any circulating rabbit IgG, the animals are challenged with mouse-anti rabbit IgG. This leads to a dose-dependent renal injury mediated by complement induced neutrophil recruitment. When IdeS was given between the two IgG injections, it completely inhibited the development of proteinuria. Histological examinations confirmed that Fc fragments but not F (ab’)2 fragment had been removed from the GBM. This was accompanied by a reduction in the deposition of complement and influx of neutrophils in the glomeruli. EndoS was also employed in this model, even though the setup is not ideal for testing EndoS a positive effect was seen. EndoS has also been used in a model of Rabbit Polyclonal to GPR174 ANCA associated vasculitis (32). Pre-treatment of human MPO-ANCA containing IgG with EndoS prevented neutrophil respiratory burst. When mouse anti-MPO was exposed to EndoS before injection into mice, the antibodies did not induce disease. In addition, when EndoS was given to the mice after challenge with anti-MPO IgG antibodies this attenuated the disease (32). IdeS in Humans In a phase I trial, IdeS was given in different doses to healthy human volunteers.