Modern transplantation has relied greatly on the concept of brain death and the use of brain-dead donors. With the increased understanding of brain death-related pathophysiology, it is now clear that brain death itself can cause injury to the donor organs (1). A “storm” of catecholamines and cytokines accompanies brain death and leads to a generalized systemic inflammatory response. Yet, the exact mechanism for the brain death induced inflammatory responses remains to be elucidated. Key players of the inflammatory response (cytokines, chemokines, and other inflammatory mediators) are generated by the innate immune system after the recognition of molecular patterns deemed harmful to the host. The best studied example of pattern recognition receptors to date is the toll-like receptors (TLRs). Activation of TLRs may result in the activation of NF-κB and the subsequent release of proinflammatory cytokines and the induction of co-stimulatory molecules. Thus, TLRs can bridge innate and adaptive immune responses; certainly, something of interest to transplant clinicians. Initially believed of only as sensors of exogenous or pathogenic molecular patterns, there is now increasing evidence that TLRs can sense host tissue damage (2). Molecules typically confined to the intracellular space such as HMGB1, hyaluronan, and S100 have been found to be able to bind and activate TLRs. Tissue damage is an obligatory part of organ transplantation and thus TLRs likely play a role in the activation of inflammation and priming of the acute immune response after transplantation. In studies of TLRs within the context of transplantation, a reduction of ischemia-reperfusion injury in the lung (3), liver, and kidney as well as reduced antigen presenting cell activation in a skin transplantation model have been found. Living-donor kidneys express less HMGB1 than brain-dead donor kidneys in clinical kidney transplantation. Recipients of kidney grafts from donors with loss-of-function single nucleotide polymorphisms in TLR4, Asp299Gly, and Thr399Ile had superior immediate graft function and lower intragraft proinflammatory gene expression. Thus, TLRs seem to play a role in mediating donor organ injury, but until now the link between brain death and the function of TLRs has not been well studied in the lung transplant setting (4). Rostron et al., (5) in this issue of Transplantation, assess the donor TLR response to brain death using a rat model. Brain death was induced by the previously described method of balloon inflation in the epidural space, and TLR4 and TLR2/6 desensitization was induced by 5 days of TLR agonist treatment and then observed for 3 days before brain death induction. After brain death induction, rats with prior TLR desensitization showed a better preserved mean arterial pressure after brain death, decreased cytokine expression, and reduced expression of CD11b/CD18 adhesion molecules by neutrophils in the blood (5). This is an important first look at the effect of donor brain death on the activation of donor organ TLRs. Their data suggest that TLRs can mediate organ dysfunction after brain death, yet the mechanism remains elusive. Further study with more targeted TLR pathway knockouts may help clarify the mechanism. Recently, the parasympathetic nervous system has been shown to be involved in modulation of the innate immune system. Could loss of vagus nerve stimulation cause HMGB1 secretion? What is the ligand released during brain death leading to TLR activation? Are these effects seen posttransplant? Fortunately, many of the tools needed to start to answer these questions are now available. A variety of TLR and TLR adaptor knockout mice have been generated. Moreover, lung transplantation in mice has now been reported. A better understanding of how this first injury of brain death can activate innate immunity will hopefully lead to reduced organ inflammation and priming of adaptive immunity in the recipient. Further study of this phenomenon is warranted.
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Jul 16, 2017
Sheri Tran + 1
Open Access