All allografts suffer a number of unavoidable ischemic insults. These, starting with brain death and ending with reperfusion, are very troublesome, as ischemia-reperfusion injury (IRI) is demonstrated to be a major cause of allograft damage in various types of transplantations. To counter the threat this poses to allograft function, investigators have worked diligently over the past decades in clinical settings and in the laboratory to understand the pathophysiology and immune mechanism underlying IRI hoping to ultimately devise strategies that lessen its detrimental effects on allografts. Herein, we review the major immune components of the IRI dynamic process. Better understanding of the cellular pathophysiological processes underlying IRI will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive allograft damage.
During transplantation procedures, allografts are exposed to various periods of complete ischemia; ischemic insults start with brain death and its associated hemodynamic disturbances (elevated intracranial pressure; bradycardia; decreased cardiac output) continue during donor organ procurement, cold preservation, and implantation. Following reperfusion, ischemia-reperfusion injury (IRI) is triggered; this could potentially lead to allograft damage (delayed graft function, acute and chronic rejection), posing serious threats to transplant recipients. Along the cascade of pathogenic events that accompany ischemic insults and cause IRI, there has been an appreciation for various immune mechanisms within the allograft itself and their role in priming the allograft for further injury. Free radical-mediated injury releases proinflammatory cytokines and activates the innate immune system ultimately triggering adaptive immune responses and resulting in tissue damage. The outcome of the organ depends on whether cell death or regeneration prevails. The aim of this review is to revisit these immune mechanisms at the cellular and molecular levels, and provide useful clinical recommendations aiming at overcoming the challenges of IRI.
Studies in solid organ transplantation (SOT) have shown that IRI is a potent activator of the immune system, and therefore leads to poor functional outcomes that are directly related to increasing ischemia times [1-4]. Yet ischemia is only one of several factors shown to contribute to acute and chronic rejection, as reperfusion injury further propagates and intensifies the immune response [
The strong inflammatory response induced by IRI both activates the immune system and mediates tissue injury via activation of leukocytes and endothelial cells, generation of ROS, and upregulation of adhesion molecules and inflammatory cytokines [
The activation of the immune system is mediated by endogenous stress signals and a class of primitive proteins expressed by the innate immune system. Specifically, ischemically injured tissues generate damage-associated molecular patterns (DAMPs), which are recognized by pattern-recognition receptors (PRRs) of the innate immune system leading to upregulation of inflammatory cytokines and cell adhesion molecules [
The adaptive immune system also contributes to the rejection process with the participation of TLRs that sensitize and activate antigen-presenting cells (APCs). The sensitization of APCs leads to a significant increase of effector T cells that further augments the pro-inflammatory cytokine milieu induced by IRI [12,15,16]. An elegant explanation came from Matzinger conducted a series of elegant experiments to investigate the relationship between tissue damage, innate immune responses, and relaying danger signals to the adaptive immune system via TLRs and APCs [
Activation of the complement pathway is another critical event leading to tissue injury after IRI. Indeed, complement is considered a key determinant of tissue rejection after SOT as it damages cell membranes through the formation of membrane attack complexes [6,7,9,22, 23]. The byproducts of the complement cascade also contribute to tissue rejection, as chemotactic agents such as C5a attract neutrophils to sites of IRI and anaphylatoxins (C3a, C5a) cause degranulation of mast cell and the release of histamine, which further damages tissues.
Although the primary factor leading to transplant rejection is undoubtedly the T cell alloimmune response triggered by MHC incompatibility, IRI further intensifies this response, and is believed to be the strongest secondary factor to augment graft allogenicity [24,25]. The danger signals produced by ischemic injury induce an elegant interaction of immune activation and signal transduction that predisposes transplanted tissues to immunologic recognition and rejection through upregulation of MHC II (signal 1) and costimulation (signal 2) by activation of APCs [
A clear relationship between the duration of ischemia and allograft survival has been demonstrated in large clinical trials of SOT, and it is hypothesized that this association is mediated by TLRs that are activated by ROS generated by IRI [5,33]. Ample evidence exists implicating TLRs as key contributors to the rate of acute rejection in heart [
Much information has been gleaned from elucidation of the molecular foundations of IRI, and this has served to inform our understanding of the effects of IRI at the macroscopic level.
In cardiac transplantation, for example IRI commonly occurs in the early post-transplant period, especially with prolonged ischemic time, and is characterized by hyperemia in the previously ischemic myocardium, which later becomes prone to coagulative necrosis [
In kidney transplants, allografts exposed to prolonged ischemia were prone to more acute rejection episodes in animal models and subsequent clinical trials observed the same effect on human renal transplants [
In lung and liver allografts, IRI leads to higher incidences of acute and chronic rejection [5,27]. Although there are very few studies examining IRI in vascularized composite allotransplantation, it is plausible that vascularized composite allografts may be even more susceptible to IRI given the diversity of tissue components contained within the graft [
In an era where organ shortage is a universal problem with high rates of death among patients on waiting lists, measures to prevent IRI and ensure healthier allografts and safer transplantation procedures are critical. Kidneys recovered from donors should be stored using pulsatile perfusion, allowing better protection during preservationrelated ischemia, as well as the measurement of several parameters—flow, resistance, lactate excretion, alfa GST —which may be useful to assess the extent of ischemic injury. Prevention of IRI can even be started before organ recovery by donor pretreatment. Pretreatment with antioxidants holds great promise conferring protective effects against liver IRI in a rat and mice models [49,50]. Moreover, the role of hemoxygenase-1 (HO-1, enzyme converting heme into biliverdin, carbon monoxide, and free Fe) has been extensively studied in protection from ischemia-reperfusion injury. Exposure of liver transplant recipient animals to inhaled CO decreased serum alanine transferase, hepatocyte necrosis, and neutrophil infiltrates in dose-dependent fashion [
In the human setting, it has been shown that cyclosporine inhibits permeability transition and, when administered on reperfusion, decreases creatine kinase release and infarct size in humans undergoing percutaneous coronary intervention for acute cardiac ischemia [
Evidently, a greater understanding of the molecular mechanisms underlying protective pathways will pave the way for clinical trials aiming at testing different strategies for minimizing IRI.
IRI is a real threat to the success of transplantation and although some period of ischemia is unavoidable, attempts should be made to minimize it to the greatest extent possible. Clear evidence exists, linking prolonged ischemia to increased episodes of acute and chronic rejection, yet we still do not have a clear understanding of what areas of the immune system can be targeted to mitigate the effects of IRI. Future research trying to bridge this knowledge gap and identify such targets in both the innate and adaptive immune system, as well as characterization of cytokine expression responsible for mediating the effects of IRI may enable longer allograft survival and a better patient quality of life.
Publication of this article was funded the Open Access Promotion Fund of the Johns Hopkins University Libraries.