Date: Monday, June 13, 2016
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Halls C&D
- Absence of Allograft TLR4 Receptor Signaling Attenuates Early Inflammation and Promotes Survival of Allografts Subjected to Prolonged Cold Ischemic Storage
- Allograft Class II MHC and CD40 Expression Are Required for Endogenous Memory CD8 T Cell Proliferation in Cardiac Allografts Subjected to Prolonged Cold Ischemic Storage
Engagement of Toll-like receptors (TLR) by endogenous danger-associated molecular pattern ligands contributes to the intensity of tissue inflammation, including the inflammation generated during ischemia-reperfusion injury in vascularized grafts. Our previous studies have indicated that endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within hours after reperfusion and are activated to produce IFN-γ in response to donor class І MHC within 24 hrs after graft reperfusion in mice and that the intensity of this response increases within allografts subjected to prolonged cold ischemic graft storage. In highly ischemic allografts, the endogenous memory CD8 T cells can directly mediate CTLA-4Ig resistant rejection of the allografts. In this study we tested the role of graft TLR4 signaling in infiltration and activation of endogenous CD8 T cells in allografts subjected to prolonged cold ischemic storage was tested. Wild type (WT) BALBc (H-2d) or BALB/c.TLR4−/−hearts were subjected to minimal 30 min vs. prolonged 8 hrs of cold ischemic storage in University of Wisconsin solution and then transplanted to C57BL/6 (H-2b) mice. Infiltration and activation of endogenous memory CD8 T cells into allografts on day 2 post-transplant were assessed. Marked decreases in neutrophil, but not endogenous memory CD4 and CD8 T cell, infiltration were observed in the highly ischemic TLR4-/- vs. WT BALB/c allografts on day 2 post-transplant. This decrease was associated with marked decreases in intragraft mRNA expression of neutrophil, but not T cell, chemoattractants. Rejection of highly ischemic TLR4-deficient allografts was modestly but significantly extended vs. WT allografts (mean survival time, 9.8 vs. 7.0 days) and peri-transplant treatment with CTLA-4Ig promoted significantly longer survival of highly ischemic TLR4-deficient than WT allografts (MST, 21.8 vs. 17.3 days). Treatment with CTLA-4Ig in B6 recipients depleted of CD8 T cells resulted in a marked prolongation in survival of TLR4-deficient vs. WT allografts (MST, 40.0 vs. 25.8 days). These data indicate that the absence of TLR4 signaling in allografts subjected to prolonged cold ischemic storage inhibits specific components of the early post-reperfusion inflammation and constitutes a barrier to graft prolonging strategies.
CITATION INFORMATION: Yagisawa T, Kohei N, Kish D, Fairchild R. Allograft TLR4 Receptor Signaling Induces Specific Early Inflammatory Events in Promotes Allografts Subjected to Prolonged Cold Ischemic Storage. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Yagisawa T, Kohei N, Kish D, Fairchild R. Allograft TLR4 Receptor Signaling Induces Specific Early Inflammatory Events in Promotes Allografts Subjected to Prolonged Cold Ischemic Storage. [abstract]. Am J Transplant. 2016; 16 (suppl 3). http://atcmeetingabstracts.com/abstract/allograft-tlr4-receptor-signaling-induces-specific-early-inflammatory-events-in-promotes-allografts-subjected-to-prolonged-cold-ischemic-storage/. Accessed December 18, 2017.
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