Project Details
Projekt
Chimeric antigen receptor (CAR) T cells as therapeutic agents for ANCA-induced Vasculitis
Subject Area
Nephrology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 525529852
This project focuses on the development of a novel treatment strategy for ANCA-associated vasculitides (AAV). AAV is an autoimmune disease in which different white blood cells are involved. On one hand, B and T cells lose their ability to differentiate between own and foreign and thus react to the body’s own molecules, namely to the enzymes myeloperoxidase (MPO) or proteinase 3 (PR3). On the other hand neutrophil granulocytes and monocytes are activated by ANCA IgG and amplify the inappropriate immune response. These cells are the main sources of the two autoantigens MPO and PR3 and binding of ANCA IgG (Antineutrophilic cytoplasmic antibodies) results in their activation. This triggers various inflammatory processes, including the oxidative burst, in which reactive oxygen species (ROS) are formed with the involvement of MPO. Persistent inflammation of the vascular tissue finally causes end organ damage. In principle, any organ can be affected, most often it concerns the kidneys, lungs or skin. Currently, a combination therapy consisting of glucocorticoids for a general anti-inflammatory effect and additionally either general cytotoxic drugs or, more specifically, rituximab for the elimination of antibody-producing B cells, is used. This treatment method suppresses the immune system and leads to potential serious side effects, such as a increased susceptibility to infectious diseases. In this project, we aim to establish CAR-T (chimeric antigen receptor) cells as novel experimental treatment strategy in a preclinical AAV animal model. Initially, CAR-T cells equipped with a chimeric antigen receptor (CAR) directed against CD19-expressing cells will be tested as treatment of AAV. Furthermore, we aim to develop a MPO-specific chimeric autoantibody receptor (MPO-CAAR) that selectively binds to und depletes B cells that produce MPO-specific autoantibodies. In an initial preliminary experiment using our preclinical murine animal model of necrotizing crescentic glomerulonephritis (NCGN) we have already collected promising data for CD19 CAR T cells as a novel therapy option: CAR T cells were detectable two and five weeks after transplantation, the B-cell content was reduced after five weeks and the anti-MPO titer were reduced. Furthermore, the pathological charateristics of the disease, namely the proportion of crescentic and necrotic glomeruli in the kidneys, were reduced. The aim of this project is to build on our preliminary data and increase the number of analyzed animals and study a longer disease course to establish a long-term therapeutic effect. Furthermore, CAR constructs with different (co-) stimulatory domains will be analyzed to identify the one with the highest effectivity. Finally, a specific therapeutic approach, namely the development and use of MPO-specific CAAR-T cells, should help to avoid the side effects of a general B-cell depletion by preventing the general suppression of the immune system.
DFG Programme
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