Effective prevention and treatment of CD8 T cell-mediated graft-versus-host-like disease (GvHD) using a JAK inhibitor. (51.3)

Abstract

Abstract A Janus kinase (JAK) inhibitor, tofacitinib (tofa), inhibits JAK 1, 2 and 3 of some cytokine receptor pathways, affects CD4+ T cell respnses, and is being tested in more than 20 clinical trials in autoimmune diseases.To determine if tofa affects CD8+ T cells, we analyzed its effect on a CD8+ T-cell-dependent murine model of GvHD (OT-I T cell transfer into Tg mice expressing ovalbumin (OVA) in their skin and mucosae). Tofa at 50 mg/kg/day (50) p.o. completely prevented GvHD development in our model vs. vehicle-treated mice with final weights: -0.6%±5.6 and -15.4%±4.1 (p<0.01; 2-way ANOVA) and clinical scores: 0 and 7.3±0.52 (p<0.01; U test) 13 days post OT-I cell transfer. Mice treated with tofa 50 starting at day 5 were completely rescued, with no clinical signs of GVHD. FACS analysis demonstrated reduced expression of OVA-specific TCR and reduced activation of OT-I cells in skin-draining lymph nodes from mice transferred with GFP/OT-I cells and treated with tofa 50 vs. vehicle alone. Tofa inhibited proliferation of OT-I cells stimulated by SIINFEKL (OVA peptide) in vitro. qRT-PCR showed increased chemokine mRNA (CXCL9; 39-fold and CXCL10; 22-fold) in the epidermis of vehicle-treated mice vs. tofa 50-treated mice 4 days post OT-I cell transfer. The effect of tofa could be explained by its inhibition of JAK signaling in IL-2 and IL-15 receptor-pathways of OT-I cells and in IFN-γ receptor-pathways of keratinocytes and tofa may thereby be effective in autoimmune diseases.