Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.
Bibliographical noteFunding Information:
We thank Carla Forsythe for excellent administrative support in the generation of this manuscript. The authors are supported by multiple grants from the National Institutes of Health (R01HL122489 and R21AI121981: H.R.T.); R01AI34495 and R01HL56067: B.R.B.); T32HL007062 (D.K.R.) and T32AI074490 (B.M.M.). Further funding was derived from an American Society of Transplantation/Pfizer Basic Science Faculty Development Grant (H.R.T.) and American Heart Association Grant (#14GRNT20400004; H.R.T.).
© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons
- basic (laboratory) research/science
- bone marrow/hematopoietic stem cell transplantation
- cytokines/cytokine receptors
- graft-versus-host disease (GVHD)
- heart transplantation/cardiology
- innate immunity
- translational research/science