JAK-STAT Inhibition in GVHD

The allo-reactive T-cell response of acute GVHD targets three principle organs: skin, gastrointestinal tract and liver. Janus kinases, or JAKs, are intracellular signaling molecules important for immune cell regulation and the pathogenesis of Graft Versus Host Disease. JAKs transduce pro-inflammatory cytokine signals that regulate the GVHD process including dendritic cell activation and T-cell trafficking, proliferation, and differentiation. Many pro-inflammatory cytokines such as interferon gamma, interleukin-6, and interleukin-2 signal through JAKs. Inhibition of JAKs can blunt signaling of the pro-inflammatory cytokines critical for GVHD development, leading to altered chemokine receptor expression on T-cells, decreased activation of antigen presenting cells, and, ultimately, reduced GVHD-induced organ damage.