Cyclical Ischaemic Preconditioning Modulates the Adaptive Immune Response in Human Limb Ischaemia-Reperfusion Injury

Abstract

Conclusion: Limb reperfusion injury can be modulated by ischemic preconditioning. Summary: Ischemic preconditioning of reperfused tissues occurs when tissues are exposed for a short period to ischemia and then followed by a recovery period free of the stimulus. This seems to render them more resistant to subsequent ischemia-reperfusion injury. Mechanisms of ischemic preconditioning are poorly understood. It is known that ischemia and ischemic preconditioning can have effects on both innate and adaptive immune systems. In this study, the authors hypothesize modulation of T-cell function may be a mechanism by which ischemic preconditioning confers protection against reperfusion injury. The authors evaluated systemic T-cell populations for their function and activation in patients undergoing anterior cruciate ligament repair using a tourniquet. Patients were included if they had no other comorbidities, took no regular medication, and were otherwise healthy. There were 25 patients randomized to preconditioning or control. In patients undergoing ischemic preconditioning during anterior cruciate repair, the leg operated on was elevated and exsanguinated; then, the tourniquet was inflated to at least 100 mm Hg greater than systolic blood pressure. Inflation was maintained for 5 minutes and then released for 5 minutes. Two further cycles of preconditioning were performed in the treated patients. In control patients, a tourniquet was applied but was not inflated before the actual inflation of the tourniquet for the operation. Systemic levels of interleukin (IL) 4 and interferon-γ and surface expression of CD45ro/ra and CD62L and CD95 were measured. T cells were examined systemically and in simulated serum co-culture to determine CD4/CD8 and Th1/Th2 shifts through intercellular cytokine production. Without ischemic preconditioning, CD4 and CD45ro cell numbers increased after reperfusion injury. CD8 cells expressing CD45ro and CD95 increased with ischemic preconditioning. Preconditioning serum in co-culture attenuated increases in CD4 and decreases in CD8 cell numbers. After reperfusion injury, IL-2 levels were lower after ischemic preconditioning. Co-culture with post-reperfusion injury serum increased proinflammatory intercellular cytokine production. Comment: The data indicate ischemic preconditioning prevents lymphocyte-directed immune dysfunction through activation and proinflammatory cytokine production by CD4 cells, at the same time preventing CD4/CD8 cellular derangement. The systemic cellular and cytokine changes observed lend support to a possible role for circulating lymphocytes in remote ischemic preconditioning. (Remote ischemic preconditioning is where ischemia is administered to tissues that will not themselves undergo reperfusion injury.) Patients likely to have a marked reperfusion injury may be considered for remote ischemic preconditioning while their urgent ischemic condition is being treated.