The therapeutic use of Bruton tyrosine kinase inhibitors in Shiga toxin-mediated HUS.
New insights published on the therapeutic potential of Bruton tyrosine kinase inhibitors (BTKi) in Shiga toxin-induced hemolytic uremic syndrome.
27.02.2023

Hemolytic uremic syndrome (HUS) is a serious disorder that can develop following oral infection with Shiga toxin (Stx)-producing Escherichia coli (STEC). In this case, HUS is clinically manifested by the symptom triad of platelet deficiency (thrombocytopenia), microangiopathic hemolytic anemia (deficiency of red blood cells due to their destruction at thrombi in the small vessels), and acute renal failure. Stx-induced renal damage also triggers an immune response that causes immune cell migration (e.g., neutrophils, macrophages, and T lymphocytes) and that may further damage the kidney. The enzyme Bruton's tyrosine kinase (BTK), primarily expressed in immune cells, is involved in immune cell maturation and function. Overactivation of BTK has already been identified as a cause of several B-cell lymphomas, leading to the approval of BTK inhibitors as a therapeutic intervention for humans.
In cooperation with the research groups of Prof. Kerstin Amann and Prof. Christoph Daniel (Erlangen), Prof. Christoph Thiemermann (London) and Prof. Florian Gunzer (Dresden), members of the NWG Translational Septomics (head: Prof. Dr. med. Sina M. Coldewey, PhD) have investigated in the murine HUS model whether BTK inhibotors could be used as a therapeutic intervention also in HUS in the future.
The researchers conclude that inhibition of BTK with ibrutinib or acalabrutinib leads to an attenuated disease course in HUS, possibly due to reduced infiltration of neutrophils and macrophages into the kidney. In addition, the spleen might play a role in the pathophysiology of HUS.
The findings were published in the journal Frontiers in Immunology.
Kröller S, Wissuwa B, Dennhardt S, Krieg N, Thiemermann C, Daniel C, Amann K, Gunzer F and Coldewey SM (2023) Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome. Front. Immunol. 14:1105181. doi: 10.3389/fimmu.2023.1105181