Transplantation and Damage-Associated Molecular Patterns (DAMPs)
2016; Elsevier BV; Volume: 16; Issue: 12 Linguagem: Inglês
10.1111/ajt.13963
ISSN1600-6143
AutoresW. Land, Patrizia Agostinis, Stephan Gasser, Abhishek D. Garg, Andreas Linkermann,
Tópico(s)RNA Interference and Gene Delivery
ResumoUpon solid organ transplantation and during cancer immunotherapy, cellular stress responses result in the release of damage-associated molecular patterns (DAMPs). The various cellular stresses have been characterized in detail over the last decades, but a unifying classification based on clinically important aspects is lacking. Here, we provide an in-depth review of the most recent literature along with a unifying concept of the danger/injury model, suggest a classification of DAMPs, and review the recently elaborated mechanisms that result in the emission of such factors. We further point out the differences in DAMP responses including the release following a heat shock pattern, endoplasmic reticulum stress, DNA damage-mediated DAMP release, and discuss the diverse pathways of regulated necrosis in this respect. The understanding of various forms of DAMPs and the consequences of their different release patterns are prerequisite to associate serum markers of cellular stresses with clinical outcomes. Upon solid organ transplantation and during cancer immunotherapy, cellular stress responses result in the release of damage-associated molecular patterns (DAMPs). The various cellular stresses have been characterized in detail over the last decades, but a unifying classification based on clinically important aspects is lacking. Here, we provide an in-depth review of the most recent literature along with a unifying concept of the danger/injury model, suggest a classification of DAMPs, and review the recently elaborated mechanisms that result in the emission of such factors. We further point out the differences in DAMP responses including the release following a heat shock pattern, endoplasmic reticulum stress, DNA damage-mediated DAMP release, and discuss the diverse pathways of regulated necrosis in this respect. The understanding of various forms of DAMPs and the consequences of their different release patterns are prerequisite to associate serum markers of cellular stresses with clinical outcomes. Twenty years ago the danger/injury model in immunology was formulated and published, holding that the immune system does not care about self and non-self, but that it is any form of cell stress/tissue injury rather than the presence of non-self that induces immunity. The model emerged from two sources: (i) its publication by the Munich transplant group on the basis of significant data from a clinical trial in transplant patients, providing compelling evidence that tissue injury (here: allograft injury) induces immunity (here: alloimmunity-mediated allograft rejection) (1.Land W Schneeberger H Schleibner S The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants.Transplantation. 1994; 57 (et al): 211-217Crossref PubMed Google Scholar); (ii) its description by Polly Matzinger in the form of a self-coherent chain of argumentation on theoretical grounds resulting in the stringent conclusion that the "self/non-self" discrimination theory of immune responses is inappropriate (2.Matzinger P. Tolerance, danger, and the extended family.Annu Rev Immunol. 1994; 12: 991-1045Crossref PubMed Google Scholar). After the (re)discovery of the innate immune system, the model was modified by the two groups and currently holds that any cell stress, any tissue injury, even the slightest intra- or extracellular perturbation of the microenvironment activate the innate immune system, which reacts with an inflammatory response that, in the presence of "non-self" or "altered-self" antigens (or even "self"), elicits a specific adaptive immune response. The core of the danger/injury model refers to the generation of damage-associated molecular patterns (DAMPs), a term coined in the early 2000s (3.Land W. Allograft injury mediated by reactive oxygen species: From conserved proteins of Drosophila to acute and chronic rejection of human transplants—Part III: Interaction of (oxidative) stress-induced heat shock proteins with Toll-like receptor-bearing cells of innate immunity and its consequences for the development of acute and chronic allograft rejection.Transplant Rev (Orlando). 2003; 17: 67-86Google Scholar, 4.Seong SY Matzinger P. Hydrophobicity: An ancient damage-associated molecular pattern that initiates innate immune responses.Nat Rev Immunol. 2004; 4: 469-478Crossref PubMed Google Scholar), and also denoted as "danger signals" in the international literature. In fact, uric acid was identified as a danger signal in 2003 (5.Shi Y Evans JE Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (1382) Google Scholar), which was subsequently accepted as a true nonbacterial DAMP (6.Chen CJ Shi Y Hearn A MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals.J Clin Invest. 2006; 116 (et al): 2262-2271Crossref PubMed Scopus (369) Google Scholar). DAMPs are endogenous molecules that are emitted under various conditions of major cell stress or tissue injury. In analogy to pathogen-associated molecular patterns (PAMPs), DAMPs are sensed by either "classical" pattern recognition receptors (PRRs) or "non-classical" receptors found on the surface or within the cells of the innate immune system (referring to both mobile immune and sessile nonimmune cells), thereby leading to their activation. DAMPs are (1) exposed on the plasma membrane of stressed cells, or (2) actively secreted by stressed cells or cells at an early stage of apoptosis, or (3) passively released into the extracellular environment from dying plasma membrane-ruptured cells, or (4) released from the damaged extracellular matrix (7.Bianchi ME. DAMPs, PAMPs and alarmins: All we need to know about danger.J Leukoc Biol. 2007; 81: 1-5Crossref PubMed Scopus (1258) Google Scholar, 8.Rubartelli A Lotze MT. Inside, outside, upside down: Damage-associated molecular-pattern molecules (DAMPs) and redox.Trends Immunol. 2007; 28: 429-436Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar, 9.Land WG. Emerging role of innate immunity in organ transplantation, part II: Potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells.Transplant Rev (Orlando). 2012; 26: 73-87Crossref PubMed Scopus (0) Google Scholar). Importantly, DAMPs also include "homeostatic danger signals," that is, danger signals that do not derive directly from dying cells but are associated with perturbations of tissue/cell homeostasis and may signal pathological stress (10.Gallo PM Gallucci S. The dendritic cell response to classic, emerging, and homeostatic danger signals: Implications for autoimmunity.Front Immunol. 2013; 4: 138Crossref PubMed Scopus (0) Google Scholar). In the field of organ transplantation, the danger/injury model was tackled for the first time in the early 2000s (11.Land W. Postischemic reperfusion injury to allografts—a case for "innate immunity"?.Eur Surg Res. 2002; 34: 160-169Crossref PubMed Scopus (0) Google Scholar, 12.Land W. Allograft injury mediated by reactive oxygen species: From conserved proteins of Drosophila to acute and chronic rejection of human transplants. Part I: Demonstration of reactive oxygen species in reperfused allografts and their role in the initiation of innate immunity.Transplant Rev (Orlando). 2002; 16: 192-204Google Scholar, 13.Land W. Allograft injury mediated by reactive oxygen species: From conserved proteins of Drosophila to acute and chronic rejection of human transplants. Part II: Role of reactive oxygen species in the induction of the heat shock response as a regulator of innate immunity.Transplant Rev. 2003; 17: 31-44Crossref Scopus (0) Google Scholar, 14.Land WG. Ageing and immunosuppression in kidney transplantation.Exp Clin Transplant. 2004; 2: 229-237PubMed Google Scholar, 15.Land WG. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation.Transplantation. 2005; 79: 505-514Crossref PubMed Scopus (208) Google Scholar) and, more recently, comprehensively addressed in a monograph (16.Land WG. Innate Alloimmunity, Part 2. Innate Immunity and Rejection. Başkent University-Pabst Science Publishers, Ankara-Lengerich2011Google Scholar). According to currently accepted models (9.Land WG. Emerging role of innate immunity in organ transplantation, part II: Potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells.Transplant Rev (Orlando). 2012; 26: 73-87Crossref PubMed Scopus (0) Google Scholar, 16.Land WG. Innate Alloimmunity, Part 2. Innate Immunity and Rejection. Başkent University-Pabst Science Publishers, Ankara-Lengerich2011Google Scholar, 17.Wood KJ Goto R. Mechanisms of rejection: Current perspectives.Transplantation. 2012; 93: 1-10Crossref PubMed Scopus (244) Google Scholar, 18.Danobeitia JS Sperger JM Hanson MS Early activation of the inflammatory response in the liver of brain-dead non-human primates.J Surg Res. 2012; 176 (et al): 639-648Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19.Land WG. Chronic allograft dysfunction: A model disorder of innate immunity.Biomed J. 2013; 36: 209-228Crossref PubMed Scopus (17) Google Scholar, 20.Farrar CA Kupiec-Weglinski JW Sacks SH. The innate immune system and transplantation.Cold Spring Harb Perspect Med. 2013; 3: a015479Crossref PubMed Scopus (47) Google Scholar, 21.Linkermann A Hackl MJ Kunzendorf U Walczak H Krautwald S Jevnikar AM. Necroptosis in immunity and ischemia-reperfusion injury.Am J Transplant. 2013; 13: 2797-2804Crossref PubMed Scopus (137) Google Scholar, 22.Zhai Y Petrowsky H Hong JC Busuttil RW Kupiec-Weglinski JW. Ischaemia-reperfusion injury in liver transplantation—from bench to bedside.Nat Rev Gastroenterol Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (490) Google Scholar, 23.Denecke C Tullius SG. Innate and adaptive immune responses subsequent to ischemia-reperfusion injury in the kidney.Prog Urol. 2014; 24: S13-S19Crossref Scopus (32) Google Scholar, 24.Dziodzio T Biebl M Pratschke J. Impact of brain death on ischemia/reperfusion injury in liver transplantation.Curr Opin Organ Transplant. 2014; 19: 108-114Crossref PubMed Scopus (33) Google Scholar, 25.Venner JM Famulski KS Badr D Hidalgo LG Chang J Halloran PF. Molecular landscape of T cell-mediated rejection in human kidney transplants: Prominence of CTLA4 and PD ligands.Am J Transplant. 2014; 14: 2565-2576Crossref PubMed Scopus (75) Google Scholar, 26.Mori DN Kreisel D Fullerton JN Gilroy DW Goldstein DR. Inflammatory triggers of acute rejection of organ allografts.Immunol Rev. 2014; 258: 132-144Crossref PubMed Scopus (85) Google Scholar, 27.Abrahimi P Liu R Pober JS. Blood vessels in allotransplantation.Am J Transplant. 2015; 15: 1748-1754Crossref PubMed Scopus (36) Google Scholar, 28.Podestà MA Cucchiari D Ponticelli C. The diverging roles of dendritic cells in kidney allotransplantation.Transplant Rev (Orlando). 2015; 29: 114-120Crossref PubMed Scopus (12) Google Scholar, 29.Otterbein LE Fan Z Koulmanda M Thronley T Strom TB. Innate immunity for better or worse govern the allograft response.Curr Opin Organ Transplant. 2015; 20: 8-12Crossref PubMed Scopus (12) Google Scholar, 30.Hu Q Wood CR Cimen S Venkatachalam AB Alwayn IP. Mitochondrial damage-associated molecular patterns (MTDs) are released during hepatic ischemia reperfusion and induce inflammatory responses.PLoS ONE. 2015; 10: e0140105Crossref PubMed Scopus (32) Google Scholar), any injury to an allograft, in particular, the "canonical" oxidative injury as occurring in the donor under brain death condition and in the recipient during postischemic reperfusion, leads to induction of various classes of DAMPs that activate intragraft PRR-bearing cells of the donor's and recipient's innate immune system, a process that results in inflammation of the allograft. In parallel, donor-derived and recipient-derived dendritic cells (DCs), activated after uptake of alloantigens and recognition of various DAMPs by their corresponding PRRs, elicit—via the process of direct and indirect allorecognition—a robust adaptive anti-donor alloimmune response ultimately resulting in allograft rejection (9.Land WG. Emerging role of innate immunity in organ transplantation, part II: Potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells.Transplant Rev (Orlando). 2012; 26: 73-87Crossref PubMed Scopus (0) Google Scholar, 16.Land WG. Innate Alloimmunity, Part 2. Innate Immunity and Rejection. Başkent University-Pabst Science Publishers, Ankara-Lengerich2011Google Scholar, 17.Wood KJ Goto R. Mechanisms of rejection: Current perspectives.Transplantation. 2012; 93: 1-10Crossref PubMed Scopus (244) Google Scholar, 18.Danobeitia JS Sperger JM Hanson MS Early activation of the inflammatory response in the liver of brain-dead non-human primates.J Surg Res. 2012; 176 (et al): 639-648Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19.Land WG. Chronic allograft dysfunction: A model disorder of innate immunity.Biomed J. 2013; 36: 209-228Crossref PubMed Scopus (17) Google Scholar, 20.Farrar CA Kupiec-Weglinski JW Sacks SH. The innate immune system and transplantation.Cold Spring Harb Perspect Med. 2013; 3: a015479Crossref PubMed Scopus (47) Google Scholar, 21.Linkermann A Hackl MJ Kunzendorf U Walczak H Krautwald S Jevnikar AM. Necroptosis in immunity and ischemia-reperfusion injury.Am J Transplant. 2013; 13: 2797-2804Crossref PubMed Scopus (137) Google Scholar, 22.Zhai Y Petrowsky H Hong JC Busuttil RW Kupiec-Weglinski JW. Ischaemia-reperfusion injury in liver transplantation—from bench to bedside.Nat Rev Gastroenterol Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (490) Google Scholar, 23.Denecke C Tullius SG. Innate and adaptive immune responses subsequent to ischemia-reperfusion injury in the kidney.Prog Urol. 2014; 24: S13-S19Crossref Scopus (32) Google Scholar, 24.Dziodzio T Biebl M Pratschke J. Impact of brain death on ischemia/reperfusion injury in liver transplantation.Curr Opin Organ Transplant. 2014; 19: 108-114Crossref PubMed Scopus (33) Google Scholar, 25.Venner JM Famulski KS Badr D Hidalgo LG Chang J Halloran PF. Molecular landscape of T cell-mediated rejection in human kidney transplants: Prominence of CTLA4 and PD ligands.Am J Transplant. 2014; 14: 2565-2576Crossref PubMed Scopus (75) Google Scholar, 26.Mori DN Kreisel D Fullerton JN Gilroy DW Goldstein DR. Inflammatory triggers of acute rejection of organ allografts.Immunol Rev. 2014; 258: 132-144Crossref PubMed Scopus (85) Google Scholar, 27.Abrahimi P Liu R Pober JS. Blood vessels in allotransplantation.Am J Transplant. 2015; 15: 1748-1754Crossref PubMed Scopus (36) Google Scholar, 28.Podestà MA Cucchiari D Ponticelli C. The diverging roles of dendritic cells in kidney allotransplantation.Transplant Rev (Orlando). 2015; 29: 114-120Crossref PubMed Scopus (12) Google Scholar, 29.Otterbein LE Fan Z Koulmanda M Thronley T Strom TB. Innate immunity for better or worse govern the allograft response.Curr Opin Organ Transplant. 2015; 20: 8-12Crossref PubMed Scopus (12) Google Scholar, 30.Hu Q Wood CR Cimen S Venkatachalam AB Alwayn IP. Mitochondrial damage-associated molecular patterns (MTDs) are released during hepatic ischemia reperfusion and induce inflammatory responses.PLoS ONE. 2015; 10: e0140105Crossref PubMed Scopus (32) Google Scholar). In this review, we will present a brief overview about the initial oxidative allograft injury that represents the true point of origin of DAMP emission via instigation of stress responses and induction of cell death. We then attempt to provisionally classify DAMPs by briefly touching on their role in the activation of immunostimulatory DCs able to prime naïve CD4+- and CD8+ T cells. Subsequently, the major sources of their generation and emission, namely, those stress responses and distinct forms of regulated cell death (RCD) such as necroptosis, are highlighted. In a complementary continuative review (31.Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. DAMP-induced allograft and tumor rejection: the circle is closing. Am J Transplant. In press.Google Scholar), we will present evidence indicating that the scenario of DAMP-provoked allograft immunogenicity shows a striking mechanistic similarity with DAMP-evoked tumor immunogenicity; a recent understanding in oncoimmunology that has led to new strategies in modern anticancer therapy. Allografts are potentially exposed to many injuries starting from conditions in the organ donor, continue during organ preservation and end up with implantation-associated postischemic reperfusion injury (IRI) in the recipient. Consequently, two different innate immune systems, that of the donor and that of the recipient, are activated followed by mounting an intragraft sterile inflammatory response and leading to an adaptive alloimmune response in the recipient. First severe injury to an allograft occurs already in the organ donor. In particular, development of reactive oxygen species (ROS)–mediated oxidative stress under brain-death (BD) conditions is substantial as demonstrated in both experimental models and deceased organ donors. Together with the scenario of ROS-mediated IRI in the recipient, it may be regarded as the canonical injury an allograft is exposed to. A decade ago, early experiments on a rat model revealed a strong influence of BD condition on chronic graft dysfunction (32.Pratschke J Wilhelm MJ Laskowski I Influence of donor brain death on chronic rejection of renal transplants in rats.J Am Soc Nephrol. 2001; 12 (et al): 2474-2481Crossref PubMed Google Scholar). Emerging evidence now indicates that donor BD conditions, associated with oxidative stress (including oxidative stress-induced endoplasmic reticulum [ER] stress associated with apoptosis) activate the innate immune system, which leads to development of an acute systemic auto-inflammatory syndrome (24.Dziodzio T Biebl M Pratschke J. Impact of brain death on ischemia/reperfusion injury in liver transplantation.Curr Opin Organ Transplant. 2014; 19: 108-114Crossref PubMed Scopus (33) Google Scholar, 33.Kosieradzki M Kuczynska J Piwowarska J Prognostic significance of free radicals: Mediated injury occurring in the kidney donor.Transplantation. 2003; 75 (et al): 1221-1227Crossref PubMed Scopus (71) Google Scholar, 34.Schuurs TA Morariu AM Ottens PJ Time-dependent changes in donor brain death related processes.Am J Transplant. 2006; 6 (et al): 2903-2911Crossref PubMed Scopus (0) Google Scholar, 35.Stiegler P Sereinigg M Puntschart A Oxidative stress and apoptosis in a pig model of brain death (BD) and living donation (LD).J Transl Med. 2013; 11 (et al): 244Crossref PubMed Scopus (31) Google Scholar, 36.Leber B Stadlbauer V Stiegler P Effect of oxidative stress and endotoxin on human serum albumin in brain-dead organ donors.Transl Res. 2012; 159 (et al): 487-496Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 37.Morariu AM Schuurs TA Leuvenink HG van Oeveren W Rakhorst G Ploeg RJ. Early events in kidney donation: Progression of endothelial activation, oxidative stress and tubular injury after brain death.Am J Transplant. 2008; 8: 933-941Crossref PubMed Scopus (0) Google Scholar, 38.Marasco SF Sheeran FL Chaudhuri K Vale M Bailey M Pepe S. Molecular markers of programmed cell death in donor hearts before transplantation.J Heart Lung Transplant. 2014; 33: 185-193Abstract Full Text Full Text PDF PubMed Google Scholar, 39.Cao S Yan B Lu Y C/EBP homologous protein-mediated endoplasmic reticulum stress-related renal apoptosis is involved in rats with brain death.Transplant Proc. 2015; 47 (et al): 354-358Crossref Google Scholar), often associated with the demonstration of an apoptotic signature in cells of removed donor organs (kidney, heart) (38.Marasco SF Sheeran FL Chaudhuri K Vale M Bailey M Pepe S. Molecular markers of programmed cell death in donor hearts before transplantation.J Heart Lung Transplant. 2014; 33: 185-193Abstract Full Text Full Text PDF PubMed Google Scholar, 39.Cao S Yan B Lu Y C/EBP homologous protein-mediated endoplasmic reticulum stress-related renal apoptosis is involved in rats with brain death.Transplant Proc. 2015; 47 (et al): 354-358Crossref Google Scholar, 40.Birks EJ Yacoub MH Burton PS Activation of apoptotic and inflammatory pathways in dysfunctional donor hearts.Transplantation. 2000; 70 (et al): 1498-1506Crossref PubMed Google Scholar, 41.Stoica SC Satchithananda DK Atkinson C Charman S Goddard M Large SR. Heat shock protein, inducible nitric oxide synthase and apoptotic markers in the acute phase of human cardiac transplantation.Eur J Cardiothorac Surg. 2003; 24: 932-939Crossref PubMed Scopus (0) Google Scholar, 42.Pérez López S Vázquez Moreno N Escudero Augusto D A molecular approach to apoptosis in the human heart during brain death.Transplantation. 2008; 86 (et al): 977-982Crossref PubMed Scopus (10) Google Scholar, 43.Secher N Soendergaard P Ravlo K No effect of remote ischaemic conditioning on inflammation in a porcine kidney transplantation model.Transpl Immunol. 2014; 31 (et al): 98-104Crossref PubMed Scopus (6) Google Scholar, 44.Li S Loganathan S Korkmaz S Transplantation of donor hearts after circulatory or brain death in a rat model.J Surg Res. 2015; 195 (et al): 315-324Abstract Full Text Full Text PDF PubMed Google Scholar). In fact, documented parameters involved in BD-activated innate immune events include DAMPs (45.Arbogast H Arbogast S Fertmann J Expression of heat shock proteins in cadaveric human renal allografts—A role in activation of innate immunity?.Transplantation. 2002; 74 (et al): 266Google Scholar, 46.Krüger B Krick S Dhillon N Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation.Proc Natl Acad Sci USA. 2009; 106 (et al): 3390-3395Crossref PubMed Scopus (0) Google Scholar, 47.Saat TC Susa D Kok NF Inflammatory genes in rat livers from cardiac- and brain death donors.J Surg Res. 2015; 198 (et al): 217-227Abstract Full Text Full Text PDF PubMed Google Scholar), upregulated PRRs and signaling molecules (46.Krüger B Krick S Dhillon N Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation.Proc Natl Acad Sci USA. 2009; 106 (et al): 3390-3395Crossref PubMed Scopus (0) Google Scholar, 48.Rostron AJ Cork DM Avlonitis VS Fisher AJ Dark JH Kirby JA. Contribution of toll-like receptor activation to lung damage after donor brain death.Transplantation. 2010; 90: 732-739Crossref PubMed Scopus (12) Google Scholar, 49.Chen L Xu D Gao Y Effect of donor JNK signal transduction inhibition on transplant outcome in brain dead rat model.Inflammation. 2012; 35 (et al): 122-129Crossref Scopus (9) Google Scholar), complement fragments (50.Damman J Daha MR van Son WJ Leuvenink HG Ploeg RJ Seelen MA. Crosstalk between complement and toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.Am J Transplant. 2011; 11: 660-669Crossref PubMed Scopus (0) Google Scholar), cytokines such as IL‑1β (36.Leber B Stadlbauer V Stiegler P Effect of oxidative stress and endotoxin on human serum albumin in brain-dead organ donors.Transl Res. 2012; 159 (et al): 487-496Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 51.Takada M Nadeau KC Hancock WW Effects of explosive brain death on cytokine activation of peripheral organs in the rat.Transplantation. 1998; 65 (et al): 1533-1542Crossref PubMed Scopus (366) Google Scholar, 52.Kusaka M Pratschke J Wilhelm MJ Activation of inflammatory mediators in rat renal isografts by donor brain death.Transplantation. 2000; 69 (et al): 405-410Crossref PubMed Scopus (161) Google Scholar), and upregulated chemokine receptors (18.Danobeitia JS Sperger JM Hanson MS Early activation of the inflammatory response in the liver of brain-dead non-human primates.J Surg Res. 2012; 176 (et al): 639-648Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Moreover, mature activated DCs could also be demonstrated in the blood and spleen of brain-dead organ donors (Table 1) (53.Velásquez-Lopera MM Correa LA García LF. Human spleen contains different subsets of dendritic cells and regulatory T lymphocytes.Clin Exp Immunol. 2008; 154: 107-114Crossref PubMed Scopus (0) Google Scholar, 54.Mittag D Proietto AI Loudovaris T Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status.J Immunol. 2011; 186 (et al): 6207-6217Crossref PubMed Scopus (191) Google Scholar).Table 1Association of brain death condition with parameters of innate immunityParameters of innate immunity"Innate" molecules demonstrated under brain death conditionsReferences (no.)Oxidative injuryROS (indirectly measured)(33.Kosieradzki M Kuczynska J Piwowarska J Prognostic significance of free radicals: Mediated injury occurring in the kidney donor.Transplantation. 2003; 75 (et al): 1221-1227Crossref PubMed Scopus (71) Google Scholar, 36.Leber B Stadlbauer V Stiegler P Effect of oxidative stress and endotoxin on human serum albumin in brain-dead organ donors.Transl Res. 2012; 159 (et al): 487-496Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)ComplementC3, C5b-9(50.Damman J Daha MR van Son WJ Leuvenink HG Ploeg RJ Seelen MA. Crosstalk between complement and toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.Am J Transplant. 2011; 11: 660-669Crossref PubMed Scopus (0) Google Scholar)DAMPsHMGB1, HSP70(45.Arbogast H Arbogast S Fertmann J Expression of heat shock proteins in cadaveric human renal allografts—A role in activation of innate immunity?.Transplantation. 2002; 74 (et al): 266Google Scholar, 47.Saat TC Susa D Kok NF Inflammatory genes in rat livers from cardiac- and brain death donors.J Surg Res. 2015; 198 (et al): 217-227Abstract Full Text Full Text PDF PubMed Google Scholar)PRRsTLR2, TLR4(46.Krüger B Krick S Dhillon N Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation.Proc Natl Acad Sci USA. 2009; 106 (et al): 3390-3395Crossref PubMed Scopus (0) Google Scholar, 48.Rostron AJ Cork DM Avlonitis VS Fisher AJ Dark JH Kirby JA. Contribution of toll-like receptor activation to lung damage after donor brain death.Transplantation. 2010; 90: 732-739Crossref PubMed Scopus (12) Google Scholar)Signaling moleculesNF-κB, JNK1Demonstrated in experimental models of brain death only.(35.Stiegler P Sereinigg M Puntschart A Oxidative stress and apoptosis in a pig model of brain death (BD) and living donation (LD).J Transl Med. 2013; 11 (et al): 244Crossref PubMed Scopus (31) Google Scholar, 44.Li S Loganathan S Korkmaz S Transplantation of donor hearts after circulatory or brain death in a rat model.J Surg Res. 2015; 195 (et al): 315-324Abstract Full Text Full Text PDF PubMed Google Scholar, 49.Chen L Xu D Gao Y Effect of donor JNK signal transduction inhibition on transplant outcome in brain dead rat model.Inflammation. 2012; 35 (et al): 122-129Crossref Scopus (9) Google Scholar)CytokinesIL-1β, IL-6, TNF(36.Leber B Stadlbauer V Stiegler P Effect of oxidative stress and endotoxin on human serum albumin in brain-dead organ donors.Transl Res. 2012; 159 (et al): 487-496Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44.Li S Loganathan S Korkmaz S Transplantation of donor hearts after circulatory or brain death in a rat model.J Surg Res. 2015; 195 (et al): 315-324Abstract Full Text Full Text PDF PubMed Google Scholar, 48.Rostron AJ Cork DM Avlonitis VS Fisher AJ Dark JH Kirby JA. Contribution of toll-like receptor activation to lung damage after donor brain death.Transplantation. 2010; 90: 732-739Crossref PubMed Scopus (12) Google Scholar, 51.Takada M Nadeau KC Hancock WW Effects of explosive brain death on cytokine activation of peripheral organs in the rat.Transplantation. 1998; 65 (et al): 1533-1542Crossref PubMed Scopus (366) Google Scholar, 52.Kusaka M Pratschke J Wilhelm MJ Activation of inflammatory mediators in rat renal isografts by donor brain death.Transplantation. 2000; 69 (et al): 405-410Crossref PubMed Scopus (161) Google Scholar)Chemokine receptorsCxCR1, CxCR2(18.Danobeitia JS Sperger JM Hanson MS Early activation of the inflammatory response in the liver of brain-dead non-human primates.J Surg Res. 2012; 176 (et al): 639-648Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)Adhesion moleculesICAM1Demonstrated in experimental models of brain death only.(18.Danobeitia JS Sperger JM Hanson MS Early activation of the inflammatory response in the liver of brain-dead non-human primates.J Surg Res. 2012; 176 (et al): 639-648Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)Dendritic cellsMature DCs(53.Velásquez-Lopera MM Correa LA García LF. Human spleen contains different subsets of dendritic cells and regulatory T lymphocytes.Clin Exp Immunol. 2008; 154: 107-114Crossref PubMed Scopus (0) Google Scholar, 54.Mittag D Proietto AI Loudovaris T Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status.J Immunol. 2011; 186 (et al): 6207-6217Crossref PubMed Scopus (191) Google Scholar)CxCR, C–X–C motif receptor; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; HMGB1, high mobility group box 1; HSP70, heat shock protein 70; ICAM, intracellular adhesion molecule 1; JNK, c-Jun NH(2)-terminal kinase; NF-κB, nuclear factor kappaB; PRRs, pattern recognition receptors; ROS, reactive oxygen species; TLR, Toll-like receptor; TNF, tumor necrosis factor.1 Demonstrated in experimental models of brain death only. Open table in a new
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