Innate Immune Responses and Bronchiolitis Obliterans Syndrome

Abstract

The innate immune system, central to host defense, is now recognized to play a critical role in regulating adaptive immune responses, including allograft rejection. Innate immunity is of particular importance in lung transplantation, given the specialized innate defense mechanisms within the lung and the constant interaction between the allograft and the external environment. A central principle of innate immunity is the recognition of highly conserved molecular patterns present on microbial pathogens or injured tissue by host innate pattern recognition receptors (PRRs). The Toll-like receptors (TLRs) are the best described and most extensively studied PRRs of relevance to transplant rejection. For example, in animal models, genetic inhibition of TLR signaling attenuates allograft rejection, while TLR activation impedes successful transplant tolerance. These findings have been translated into clinical lung transplantation, as we have shown that functional polymorphisms in the innate receptors TLR4 and CD14 impact the risk for acute rejection and bronchiolitis obliterans syndrome (BOS). Consequently, a more complex view of BOS pathogenesis that considers the influence of previously identified clinical risk factors on activation of both innate and adaptive immunity has emerged. While additional studies are needed to define the full spectrum of innate ligands and PRRs relevant to lung transplantation, it is clear that innate mechanisms are likely to play a central role in mediating lung allograft rejection and BOS. Selective inhibition of innate pathways represents an attractive approach that could complement existing immunosuppressive strategies to reduce rejection after lung transplantation.