Innate Immunity-Mediated Allograft Rejection and Strategies to Prevent It

Experimental and clinical evidence has accumulated in support of the notion that oxidative injuries to allografts induce an adaptive alloimmune response which leads to acute rejection. The link between the initial injury and subsequent rejection is the innate immune system represented by injury-activated donor-derived and recipient-derived dendritic cells which interact with naïve T cells of the recipient to induce an alloimmune T-cell response. Therefore, time is mature to consider potential therapeutic strategies that are able to suppress events of innate immunity. Such strategies refer to a “time-restricted therapeutic window” that includes treatment of the donor during organ removal and the recipient during allograft reperfusion. Major targets of such treatment include (1) mitigation of the oxidative allograft injury; (2) inhibition of injury-induced activation of complement; (3) inhibition of Toll-like receptor (TLR)-mediated and innate lymphocyte-triggered maturation of dendritic cells; and (4) blockade of innate effector functions. A considerable variety of promising experimental studies about the prevention/inhibition of innate immune events has already been performed, including the successful experimental use of gene silencing methods, eg, using RNA interference technology with the application of small interfering RNA (siRNA). In addition, a few clinical trials with antioxidants (edaravone, SOD-mimetics), complement inhibitors (pexelizumab, TP-10) in patients with acute myocardial infarction, and TLR4 antagonists (TAK-242, E-5564) in patients with sepsis have been performed or are underway. Performance of similar clinical trials in transplant patients with antioxidative drugs, complement inhibitors, and/or TLR4 antagonists is urgently warranted; siRNAs appear to be extremely attractive for investigation in experimental allogeneic transplant models.