Repurposing Jak/STAT Signaling Inhibition to Enhance Costimulation Blockade and Promote Transplant Acceptance
Plastic and Reconstructive Surgery, Johns Hopkins University, Baltimore.
Meeting: 2015 American Transplant Congress
Abstract number: 241
Keywords: Co-stimulation, Jak/STAT, T cell activation
Session Information
Session Name: Concurrent Session: Transplant Tolerance: Animal Models I
Session Type: Concurrent Session
Date: Monday, May 4, 2015
Session Time: 2:15pm-3:45pm
Presentation Time: 2:15pm-2:27pm
Location: Room 121-C
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 CD28- and CD40-independent manner. We then aimed to delineate the possible synergism between CD28 blockade and inhibition of cytokine signaling via JAK/STAT inhibition.
METHODS: Murine T cell activation was assessed via quantification of early IL-2 secretion and through a CFSE proliferation assay. Stimulation in an inflamed environment was simulated through addition of supernatant (MATSup) from maturing dendritic cells (following exposure to LPS). Inflammatory cytokines signaling inhibition was exerted with the Jak3/1 inhibitor Tofacitinib (Tofa). Differential expression of DC maturation markers in response to LPS +/- Tofa 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: Activation-associated IL-2 production by T cells was diminished by CTLA4-Ig, as expected. The presence of MATSup, however, completely abolished this effect. Similarly, MATSup counteracted the anti-proliferative effect of CTLA4-Ig on both CD4 and CD8 T cells in our CFSE-proliferation assay. Notably, Tofa addition was able to completely restore CTLA4-Ig inhibition in presence of MATSup. Tofa also impacted DC by reducing their maturation (e.g. upregulation of CD40, CD80, and CD86 and accumulation of IL-6, IL-1, and TNF-α) in response to LPS. Our heart transplant model showed that 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). Extended survival was associated to lower Th1 cell differentiation and higher proportion of graft infiltrating Treg. Surprisingly, this improvement was even stronger in mice receiving hearts kept ischemic for 4h before transplantation (a more clinically relevant scenario): MST CTLA4-Ig only: 26.5d, Tofa+CTLA4-Ig: 4/5 vital grafts at 140d (currently ongoing).
CONCLUSION: 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 regulation of transplant rejection.
To cite this abstract in AMA style:
Raimondi G, Khalifian S, Miller D, Oh B, Furtmueller G, Fryer M, Lee W, Brandacher G. Repurposing Jak/STAT Signaling Inhibition to Enhance Costimulation Blockade and Promote Transplant Acceptance [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/repurposing-jakstat-signaling-inhibition-to-enhance-costimulation-blockade-and-promote-transplant-acceptance/. Accessed May 19, 2025.« Back to 2015 American Transplant Congress