Figure 4.

Blockade of Inositol 1,4,5-triphosphate 3-kinase B (ITPKB) as a novel treatment for Graft-versus-Host Disease. TCR stimulation activates downstream PLCγ, thereby increasing intracellular IP₃ levels. Binding of IP₃ to IP₃R activates the release of Ca²⁺ from intracellular storage compartments. Furthermore, STIM stimulate the influx of extracellular Ca²⁺ to activate NFAT signaling and gene transcription. ITPKB is a rate-limiting step as it catalyzes the formation of IP₄ from IP₃. IP₄ acts as a control mechanism for calcium signaling by blocking the respective channels in the extracellular membrane. Genetic deletion or inhibition of ITPKB disturbs this control mechanism and leads to increased calcium influx, which stimulates pro-apoptotic signaling pathways, leading to activation-induced cell death. Since ITPKB is predominantly found in hematopoietic cells, this kinase is thought to be a novel target molecule for the treatment of GvHD. Adapted from “NFAT Signaling Pathway”, by Biorender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.