Danger signals in regulating the immune response to solid organ transplantation

Abstract

Endogenous danger signals, or damage-associated molecular patterns (DAMPs), are generated in response to cell stress and activate innate immunity to provide a pivotal mechanism by which an organism can respond to damaged self. Accumulating experimental and clinical data have established the importance of DAMPs, which signal through innate pattern recognition receptors (PRRs) or DAMP-specific receptors, in regulating the alloresponse to solid organ transplantation (SOT). Moreover, DAMPs may incite distinct downstream cellular responses that could specifically contribute to the development of allograft fibrosis and chronic graft dysfunction. A growing understanding of the role of DAMPs in directing the immune response to transplantation has suggested novel avenues for the treatment or prevention of allograft rejection that complement contemporary immunosuppression and could lead to improved outcomes for solid organ recipients.

Figure 1. Danger signals in solid organ transplantation (SOT).

In the context of SOT, DAMPs can accumulate in the donor organ during the process of donor brain death or as a result of IRI. DAMPs act through TLRs or DAMP-specific receptors to activate innate immunity and enhance the alloresponse by upregulating donor alloantigen presentation, providing costimulation to recipient T cells and driving effector T cell recruitment and differentiation. Cytotoxic T cells and donor-specific antibody generated from the alloresponse can cause acute allograft rejection, which may in turn cause sustained graft injury, thereby potentiating DAMP release. Evolving data suggest DAMPs may also directly promote fibrotic responses, thereby potentially contributing, along with alloimmunity, to the development of organ fibrosis and chronic graft dysfunction.