Prolonged Cold Ischemia Increases the Early Infiltration and Effector Functions of Memory CD8 T Lymphocytes in Cardiac Allografts
Immunology, Cleveland Clinic, Cleveland, OH
Meeting: 2013 American Transplant Congress
Abstract number: 164
Introduction: During organ transplantation, ischemia-reperfusion injury (IRI) is an inescapable challenge that detrimentally impacts graft outcome. While I/R induced molecular mechanisms mediating injury of ischemic tissues are increasingly being delineated, cellular elements contributing to IRI remain poorly understood. The presence of pre-existing alloreactive memory T cells in the recipient is now widely recognized as a major barrier to tolerance induction and maintenance. We have reported that endogenous memory CD8 T cells with donor-reactivity infiltrate cardiac allografts within 24hrs of reperfusion and are activated to produce IFN-Γ. The mechanisms promoting infiltration of these T cells into the graft and their activities impacting graft function and survival remain poorly defined.
Methods: A/J (H-2a) hearts were subjected to 0.5hrs, 4hrs, or 8hrs of cold ischemia in UW solution before being heterotopically transplanted to C57BL/6 (H-2b) recipients.
Results: CD8+CD62Llow memory T cell infiltration into cardiac allografts at 48hrs post-transplant was significantly influenced by the duration of ischemia imposed on the graft. A mean of 3.0×104 cells/g were found to infiltrate allografts after 0.5hrs of cold ischemia that increased to 7.5×104 cells/g and 10.6×104 cells/g after 4 and 8hrs, respectively. Prolonged ischemia increased graft expression of IL-1, IL-6, and TNFΑ 48hrs after reperfusion and anti-TNFΑ or anti-IL-6 treatment at reperfusion significantly inhibited CD8 memory infiltration. Prolonged ischemia resulted in a 40-60 fold increase in IFN-Γ and perforin production by early graft infiltrating memory CD8 T cells and the heightened infiltration and effector functions of these cells was associated with markedly increased graft inflammation and myocyte damage at day 5 post-transplant. Furthermore, while treatment with CTLA4-Ig significantly prolonged survival of grafts subjected to minimal cold ischemia (MST=20.5), grafts subjected to prolonged ischemia were minimally sensitive to treatment with CTLA4-Ig (MST=d11) and this result was dependent on early memory CD8 infiltration.
Conclusion: These data demonstrate that prolonged ischemic insult to cardiac allografts enhances the early infiltration and effector functions of CD8 memory T cells post-transplant to mediate tissue inflammation and organ dysfunction. These studies provide novel insights into mechanisms underlying the poor outcomes associated with cadaver donor grafts.
To cite this abstract in AMA style:
Su C, Iida S, Abe T, Fairchild R. Prolonged Cold Ischemia Increases the Early Infiltration and Effector Functions of Memory CD8 T Lymphocytes in Cardiac Allografts [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/prolonged-cold-ischemia-increases-the-early-infiltration-and-effector-functions-of-memory-cd8-t-lymphocytes-in-cardiac-allografts/. Accessed December 2, 2024.« Back to 2013 American Transplant Congress