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Repurposing Jak/STAT Signaling Inhibition to Enhance Costimulation Blockade and Promote Transplant Acceptance
Marcos Iglesias Lozano, DVM, PhD, Saami Khalifian, MD, Byoungchol Oh, DVM, PhD, Devin Miller, BS, Georg Furtmueller, MD, Madeline Fryer, BS, W.P. Andrew Lee, MD, Gerald Brandacher, MD, Giorgio Raimondi, PhD.
Johns Hopkins School of Medicine, Baltimore, MD, USA.

PURPOSE:
Transplant tolerance induction through conventional costimulation blockade (CoB) remains an elusive goal. Recent evidence suggests that inflammatory cytokines contribute to the activation of alloreactive T cells in a costimulation-independent manner. We then aimed to delineate the possible synergism between CD28-blockade and inhibition of cytokine signaling via JAK/STAT pathway.
METHODS:
Murine T cell activation and Treg cell activity was assessed through a CFSE proliferation/supression assay respectively. Stimulation in an inflamed environment was simulated through addition of supernatant (MATSup) from maturing dendritic-cells (DC). Inflammatory cytokines signaling inhibition was exerted with the Jak3/1-inhibitor Tofacitinib (Tofa). Differential expression of DC maturation markers was analyzed by flow cytometry. In vivo synergism between Tofa and CTLA4-Ig was tested in a BALB/c-to-B6 heart graft model.
RESULTS:
MATSup counteracted the anti-proliferative effect of CTLA4-Ig on CD4/CD8 Tcells. Notably, Tofa addition was able to completely restore CTLA4-Ig-inhibition in presence of MATSup. Tofa also reduced DC maturation in response to LPS but did not interfere with Treg suppression of CD4/CD8 Tcells. Our heart transplant model showed that a short course of Tofa synergized with CTLA4-Ig promoting long-term graft survival, associated to lower Th1 cell production and an increase in graft infiltrating Treg. This improvement was even stronger in mice receiving hearts kept ischemic for 4h before transplantation.
CONCLUSIONS:
Our results clearly indicate that inflammatory cytokines counteracts the efficacy of CoB. However, their redundant activity can be neutralized repurposing Tofa. Our transplant survival data suggest that combining transient Jak-inhibition with CoB is a promising strategy for promotion of transplant acceptance.


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