Jak/STAT signaling inhibition enhances costimulation blockade and promotes transplant acceptance (TRAN1P.943)

Abstract

Abstract Transplant tolerance induction through costimulation blockade (CoB) remains an elusive goal. Recent evidence suggests that inflammatory cytokines (IC) contribute to the activation of alloreactive T cells in a CD28- and CD40-independent manner. We aimed to delineate the possible synergism between CD28 blockade and inhibition of IC signaling via Jak/STAT inhibition. First, we measured the impact on mouse T cell activation via quantification of IL-2 secreting cells at 24h post in vitro stimulation. Although CTLA4-Ig diminished the proportion of IL-2+ cells, the concomitant addition of the supernatant (MATSup) from maturing dendritic cells completely abolished this effect. This suggested an early impact of IC on T cell activation. MATSup counteracted the anti-proliferative effect of CTLA4-Ig on both CD4 and CD8 T cells. However, addition of the Jak3/1 inhibitor Tofacitinib (Tofa) completely restored the effect of CTLA4-Ig in presence of MATSup. In a BALB/c to B6 heart transplant model a short course of Tofa (d0-6) synergized with CTLA4-Ig promoting long term graft survival (MST untreated: 11d, CTLA4-Ig only: 36d, Tofa+CTLA4: 114d). Survival was associated to lower Th1 cell production and, unexpectedly, an increment in graft infiltrating Treg. Overall, our results indicate that inflammatory cytokines counteracts the efficacy of CoB. However, this effect can be neutralized via transient inhibition of Jak signaling - a promising new immunoregulatory strategy we define Enhanced CoB.