It has been shown that the treatment with ruxolitinib, which selectively blocks JAK1/2-dependent signaling pathways, resulted in a high response rate exceeding 80% among corticosteroid-refractory GVHD patients.1 It is notable, however, that IL-2-JAK3-STAT5 axis is also considered to be responsible for the therapeutic effect of ruxolitinib. IL-2-JAK3-STAT5 axis is essential for the development, survival, and proliferation of regulatory T cells (Tregs).2 The conversion of FoxP3-negative Treg-progenitor-cells into mature FoxP3-positive Tregs in the thymus occurs mediated by TCR-independent but IL-2-STAT5-dependent process.3 Ligand binding by the high affinity IL2-receptor complex results in the phosphorylation of three key tyrosine residues localized in the cytoplasmic domain of IL2-receptor-beta by both JAK1 and JAK3.2,3 Furthermore, it has been also shown that ruxolitinib suppresses the differentiation of donor T-cells into Th1/Th17 cells, while increasing the differentiation into FoxP3-positive Tregs.4 Importantly, ruxolitinib is reported to inhibit IFN-gamma signal transduction in donor T-cells, which is required for those cells to infiltrate into GVHD target organs via chemokine receptor CXCR3.5

References

1: Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29:2062-2068.

2: Mahmud SA, Manlove LS, Farrar MA. Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT. 2013;2:e23154.

3: Burchill MA, Yang J, Vang KB, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008;28:112-121.

4: Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832-3842.

5: Choi J, Ziga ED, Ritchey J, et al. IFNγR signaling mediates alloreactive T-cell trafficking and GVHD. Blood. 2012;120:4093-4103.