J Korean Soc Transplant.  2017 Sep;31(3):99-110. 10.4285/jkstn.2017.31.3.99.

Immunologic Mechanism of Ischemia Reperfusion Injury in Transplantation

• Lee JS

• KMID: 2392416
• DOI: http://doi.org/10.4285/jkstn.2017.31.3.99

Abstract

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplantation that has major consequences for graft-and patient survival. During transplantation procedures, allografts are exposed to various periods of complete ischemia. Ischemic insult starts with brain death, and its associated hemodynamic disturbances continue during donor organ procurement, cold preservation, and implantation. Ischemia-reperfusion injury, which is a risk factor for acute graft injury, delayed graft function, and acute and chronic rejection, is triggered following reperfusion. Along the cascade of pathogenic events that accompany ischemic insults and cause IRI, there has been an appreciation for various immune mechanisms within the allograft itself. The pathophysiological events associated with IRI originate in signals derived from pattern recognition receptors (PRRs) expressed in the donor organ. Danger associated molecular patterns (DAMP) released from injured cells serve as ligands for PRRs expressed on many cells in the donor organ. Activation of PRR signaling in the donor organ leads to production of proinflammatory cytokines and activates the innate immune system, triggering adaptive immune responses as well as cell death signaling, ultimately worsening the initial ischemic injury. Accordingly, deciphering the inflammatory pathway of innate immunity in IRI may provide a good therapeutic target to block acute sterile inflammation caused by tissue damage.

Keyword

Transplantation; Innate immunity; Inflammation

MeSH Terms

Allografts
Brain Death
Cell Death
Cytokines
Delayed Graft Function
Hemodynamics
Humans
Immune System
Immunity, Innate
Inflammation
Ischemia*
Ligands
Organ Transplantation
Porcine Reproductive and Respiratory Syndrome
Receptors, Pattern Recognition
Reperfusion
Reperfusion Injury*
Risk Factors
Tissue and Organ Procurement
Tissue Donors
Transplantation
Transplants
Cytokines
Ligands
Receptors, Pattern Recognition

Figure

• 

  Fig. 1 Schematic vies of innate inflammatory response. Abbreviations: DAMPs, Danger associated molecular patterns; TLRs, Toll-like receptors; TRAF6, TNF receptor-associated factor 6; MyD88, Myeloid differentiation primary response 88; TIRAP, Toll-interleukin 1 receptor (TIR) domain containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain containing adaptor protein inducing interferon; IRAK1, Interleukin 1- receptor-associated kinase 1; TBK1, TANK binding kinase 1; IKK, Inhibitor of nuclear factor kappa-B kinase; NFkB, Nuclear factor kappa B; MAP3, MAP3 kinase; IFR3, Interferon regulatory factor 3.

• 

  Fig. 2 ROS, cell stress/death, emission of DAMP axis initiating inflammation. Abbreviations: ROS, Reactive oxygen species; DAMP, Danger associated molecular pattern; PRR, pattern recognition receptor.

• 

  Fig. 3 An example of model summarizing the role of the tubular epithelial cell/NK cell/neutrophil axis in kidney IRI. Injury to TECs following IRI (step 1) promotes release of HMGB1 (step 2). This molecule stimulates TECs to produce CCR5 chemokines through TLR2 activation (step 3) in an autocrine fashion. CCR5 chemokines in turn induce NK cell recruitment (step 5). Infiltrated NK cells use their cell surface molecule CD137 to stimulate CD137L on the surface of TECs (step 6). CD137L signaling results in the production of additional signaling molecules, CXCL1 and CXCL2, in TECs (step 7). Once infiltrated (step 8), neutrophils participate in active tissue destruction (step 9). Abbreviations: CCR5, chemokine receptors 5; CD137L, CD137 ligand; CXCL1, CXC chemokine ligand 1; CXCR2, C-X-C chemokine receptor type 2; HMGB1, High mobility group box-1 protein; IR, ischemia-reperfusion; NK cells, Natural killer cells; TECs, tubular epithelial cells; TLR2, toll like receptor 2. Reprinted from Fig. 6 of reference [80].

Reference

1. Johnson KJ, Weinberg JM. Postischemic renal injury due to oxygen radicals. Curr Opin Nephrol Hypertens. 1993; 2:625–635.

2. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004; 364:1814–1827.

3. Kosieradzki M, Rowinski W. Ischemia/reperfusion injury in kidney transplantation: mechanisms and prevention. Transplant Proc. 2008; 40:3279–3288.

4. Ali S, Sheerin NS. Biomarkers of acute injury: predicting the long-term outcome after transplantation. Kidney Int. 2013; 84:1072–1074.

5. Gjertson DW, Cecka JM. Living unrelated donor kidney transplantation. Kidney Int. 2000; 58:491–499.

6. Sapir-Pichhadze R, Young A, Joseph Kim S. Living donor age and kidney transplant outcomes: an assessment of risk across the age continuum. Transpl Int. 2013; 26:493–501.

7. 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; 11:660–669.

8. Westendorp WH, Leuvenink HG, Ploeg RJ. Brain death induced renal injury. Curr Opin Organ Transplant. 2011; 16:151–156.

9. Fuquay R, Renner B, Kulik L, McCullough JW, Amura C, Strassheim D, et al. Renal ischemia-reperfusion injury amplifies the humoral immune response. J Am Soc Nephrol. 2013; 24:1063–1072.

10. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med. 2002; 8:582–587.

11. Menke J, Sollinger D, Schamberger B, Heemann U, Lutz J. The effect of ischemia/reperfusion on the kidney graft. Curr Opin Organ Transplant. 2014; 19:395–400.

12. Ponticelli C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol Dial Transplant. 2014; 29:1134–1140.

13. Ortiz F, Paavonen T, Tornroth T, Koskinen P, Finne P, Salmela K, et al. Predictors of renal allograft histologic damage progression. J Am Soc Nephrol. 2005; 16:817–824.

14. Denecke C, Tullius SG. Innate and adaptive immune responses subsequent to ischemia-reperfusion injury in the kidney. Prog Urol. 2014; 24:Suppl 1. S13–S19.

15. Cavaille-Coll M, Bala S, Velidedeoglu E, Hernandez A, Archdeacon P, Gonzalez G, et al. Summary of FDA workshop on ischemia reperfusion injury in kidney transplantation. Am J Transplant. 2013; 13:1134–1148.

16. Gueler F, Gwinner W, Schwarz A, Haller H. Long-term effects of acute ischemia and reperfusion injury. Kidney Int. 2004; 66:523–527.

17. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010; 10:826–837.

18. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009; 106:20388–20393.

19. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010; 330:362–366. Erratum in Science. 2011 Mar 25;331 (6024):1517.

20. Wahl LM, Shankavaram U, Zhang Y. Role of macrophages in vascular tissue remodelling. Transpl Immunol. 1997; 5:173–176.

21. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003; 21:335–376.

22. Callahan MK, Halleck MS, Krahling S, Henderson AJ, Williamson P, Schlegel RA. Phosphatidylserine expression and phagocytosis of apoptotic thymocytes during differentiation of monocytic cells. J Leukoc Biol. 2003; 74:846–856.

23. Lavelle EC, Murphy C, O'Neill LA, Creagh EM. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010; 3:17–28.

24. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010; 140:805–820.

25. Schroder K, Tschopp J. The inflammasomes. Cell. 2010; 140:821–832.

26. Chouchani ET, Pell VR, James AM, Work LM, Saeb-Parsy K, Frezza C, et al. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab. 2016; 23:254–263.

27. Zweier JL, Flaherty JT, Weisfeldt ML. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci U S A. 1987; 84:1404–1407.

28. Montezano AC, Touyz RM. Reactive oxygen species and endothelial function: role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol. 2012; 110:87–94.

29. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012; 298:229–317.

30. Linkermann A, Hackl MJ, Kunzendorf U, Walczak H, Krautwald S, Jevnikar AM. Necroptosis in immunity and ischemia-reperfusion injury. Am J Transplant. 2013; 13:2797–2804.

31. Silke J, Rickard JA, Gerlic M. Erratum: the diverse role of RIP kinases in necroptosis and inflammation. Nat Immunol. 2015; 16:889.

32. Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015; 22:58–73.

33. Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med. 2009; 361:1570–1583.

34. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature. 2010; 467:863–867.

35. Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J, Rath N, et al. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 2013; 20:1293–1305.

36. Mulay SR, Linkermann A, Anders HJ. Necroinflammation in Kidney Disease. J Am Soc Nephrol. 2016; 27:27–39.

37. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011; 13:184–190.

38. Finka A, Sharma SK, Goloubinoff P. Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Front Mol Biosci. 2015; 2:29.

39. Hetz C, Chevet E, Oakes SA. Proteostasis control by the unfolded protein response. Nat Cell Biol. 2015; 17:829–838.

40. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014; 3:e02523.

41. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40:179–204.

42. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009; 461:1071–1078.

43. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007; 81:1–5.

44. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007; 28:429–436.

45. Gallo PM, Gallucci S. The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013; 4:138.

46. Zhou JQ, Qiu T, Zhang L, Chen ZB, Wang ZS, Ma XX, et al. Allopurinol preconditioning attenuates renal ischemia/reperfusion injury by inhibiting HMGB1 expression in a rat model. Acta Cir Bras. 2016; 31:176–182.

47. Sugihara M, Sadamori H, Nishibori M, Sato Y, Tazawa H, Shinoura S, et al. Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy. Am J Surg. 2016; 211:179–188.

48. Venereau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. 2015; 6:422.

49. Tsung A, Tohme S, Billiar TR. High-mobility group box-1 in sterile inflammation. J Intern Med. 2014; 276:425–443.

50. Manfredi AA, Capobianco A, Bianchi ME, Rovere-Querini P. Regulation of dendritic- and T-cell fate by injury-associated endogenous signals. Crit Rev Immunol. 2009; 29:69–86.

51. Chalasani G, Li Q, Konieczny BT, Smith-Diggs L, Wrobel B, Dai Z, et al. The allograft defines the type of rejection (acute versus chronic) in the face of an established effector immune response. J Immunol. 2004; 172:7813–7820.

52. Nace G, Evankovich J, Eid R, Tsung A. Dendritic cells and damage-associated molecular patterns: endogenous danger signals linking innate and adaptive immunity. J Innate Immun. 2012; 4:6–15.

53. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012; 31:1062–1079.

54. Colombaro V, Jadot I, Decleves AE, Voisin V, Giordano L, Habsch I, et al. Lack of hyaluronidases exacerbates renal post-ischemic injury, inflammation, and fibrosis. Kidney Int. 2015; 88:61–71.

55. 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; 14:2565–2576.

56. 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; 20:8–12.

57. 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; 10:79–89.

58. Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, et al. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A. 2009; 106:3390–3395.

59. Velasquez-Lopera MM, Correa LA, Garcia LF. Human spleen contains different subsets of dendritic cells and regulatory T lymphocytes. Clin Exp Immunol. 2008; 154:107–114.

60. Chen L, Xu D, Gao Y, Cui X, Du Z, Ding Q, et al. Effect of donor JNK signal transduction inhibition on transplant outcome in brain dead rat model. Inflammation. 2012; 35:122–129.

61. 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; 90:732–739.

62. Devarajan P. Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol. 2006; 17:1503–1520.

63. Thurman JM, Royer PA, Ljubanovic D, Dursun B, Lenderink AM, Edelstein CL, et al. Treatment with an inhibitory monoclonal antibody to mouse factor B protects mice from induction of apoptosis and renal ischemia/reperfusion injury. J Am Soc Nephrol. 2006; 17:707–715.

64. Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest. 1996; 97:1056–1063.

65. Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A. 1994; 91:812–816.

66. Haug CE, Colvin RB, Delmonico FL, Auchincloss H Jr, Tolkoff-Rubin N, Preffer FI, et al. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. Transplantation. 1993; 55:766–772. discussion 772-3.

67. Salmela K, Wramner L, Ekberg H, Hauser I, Bentdal O, Lins LE, et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation. 1999; 67:729–736.

68. Kwan T, Wu H, Chadban SJ. Macrophages in renal transplantation: roles and therapeutic implications. Cell Immunol. 2014; 291:58–64.

69. Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005; 201:1135–1143.

70. Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, et al. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 2004; 173:307–313.

71. Kielar ML, John R, Bennett M, Richardson JA, Shelton JM, Chen L, et al. Maladaptive role of IL-6 in ischemic acute renal failure. J Am Soc Nephrol. 2005; 16:3315–3325.

72. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol. 1999; 277:R922–R929.

73. Wu H, Craft ML, Wang P, Wyburn KR, Chen G, Ma J, et al. IL-18 contributes to renal damage after ischemia-reperfusion. J Am Soc Nephrol. 2008; 19:2331–2341.

74. Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int. 2007; 71:619–628.

75. Alikhan MA, Jones CV, Williams TM, Beckhouse AG, Fletcher AL, Kett MM, et al. Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses. Am J Pathol. 2011; 179:1243–1256.

76. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998; 101:890–898.

77. Huen SC, Cantley LG. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol. 2015; 30:199–209.

78. Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, et al. Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low) IL-10(high) regulatory phenotype in macrophages. J Immunol. 2010; 185:2044–2050.

79. Zhang ZX, Shek K, Wang S, Huang X, Lau A, Yin Z, et al. Osteopontin expressed in tubular epithelial cells regulates NK cell-mediated kidney ischemia reperfusion injury. J Immunol. 2010; 185:967–973.

80. Kim HJ, Lee JS, Kim A, Koo S, Cha HJ, Han JA, et al. TLR2 signaling in tubular epithelial cells regulates NK cell recruitment in kidney ischemia-reperfusion injury. J Immunol. 2013; 191:2657–2664.

81. Kim HJ, Lee JS, Kim JD, Cha HJ, Kim A, Lee SK, et al. Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation. Proc Natl Acad Sci U S A. 2012; 109:E13–E22.

82. Lemley KV, Kriz W. Anatomy of the renal interstitium. Kidney Int. 1991; 39:370–381.

83. Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR, Dustin ML, et al. CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int. 2006; 70:591–596.

84. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003; 3:745–756.

85. Loverre A, Capobianco C, Stallone G, Infante B, Schena A, Ditonno P, et al. Ischemia-reperfusion injury-induced abnormal dendritic cell traffic in the transplanted kidney with delayed graft function. Kidney Int. 2007; 72:994–1003.

86. Diao H, Kon S, Iwabuchi K, Kimura C, Morimoto J, Ito D, et al. Osteopontin as a mediator of NKT cell function in T cell-mediated liver diseases. Immunity. 2004; 21:539–550.

87. Sharma AK, LaPar DJ, Zhao Y, Li L, Lau CL, Kron IL, et al. Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am J Respir Crit Care Med. 2011; 183:1539–1549.

88. Lappas CM, Day YJ, Marshall MA, Engelhard VH, Linden J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J Exp Med. 2006; 203:2639–2648.

89. Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, et al. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol. 2007; 178:5899–5911.

90. Wang S, Diao H, Guan Q, Cruikshank WW, Delovitch TL, Jevnikar AM, et al. Decreased renal ischemia-reperfusion injury by IL-16 inactivation. Kidney Int. 2008; 73:318–326.

91. Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O'Donnell MP, et al. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest. 2001; 108:1283–1290.

92. De Greef KE, Ysebaert DK, Dauwe S, Persy V, Vercauteren SR, Mey D, et al. Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia. Kidney Int. 2001; 60:1415–1427.

93. Takada M, Chandraker A, Nadeau KC, Sayegh MH, Tilney NL. The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. J Clin Invest. 1997; 100:1199–1203.

94. Shen X, Wang Y, Gao F, Ren F, Busuttil RW, Kupiec-Weglinski JW, et al. CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury. Hepatology. 2009; 50:1537–1546.

95. Satpute SR, Park JM, Jang HR, Agreda P, Liu M, Gandolfo MT, et al. The role for T cell repertoire/antigen-specific interactions in experimental kidney ischemia reperfusion injury. J Immunol. 2009; 183:984–992.

96. Ascon DB, Lopez-Briones S, Liu M, Ascon M, Savransky V, Colvin RB, et al. Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury. J Immunol. 2006; 177:3380–3387.

97. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009; 15:192–199.

98. Nadig SN, Wieckiewicz J, Wu DC, Warnecke G, Zhang W, Luo S, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010; 16:809–813.

99. Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007; 13:1299–1307.

100. Chen G, Chen S, Chen X. Role of complement and perspectives for intervention in transplantation. Immunobiology. 2013; 218:817–827.

101. van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS. Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol. 2013; 190:5921–5925.

102. Thurman JM, Ljubanovic D, Royer PA, Kraus DM, Molina H, Barry NP, et al. Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. J Clin Invest. 2006; 116:357–368.

103. Zhang M, Alicot EM, Chiu I, Li J, Verna N, Vorup-Jensen T, et al. Identification of the target self-antigens in reperfusion injury. J Exp Med. 2006; 203:141–152.

104. Kulik L, Fleming SD, Moratz C, Reuter JW, Novikov A, Chen K, et al. Pathogenic natural antibodies recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury. J Immunol. 2009; 182:5363–5373.

105. Singbartl K, Ley K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin. Crit Care Med. 2000; 28:2507–2514.

106. Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest. 1997; 99:2682–2690.

107. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int. 2002; 62:1539–1549.

108. Garcia JG. Concepts in microvascular endothelial barrier regulation in health and disease. Microvasc Res. 2009; 77:1–3.

109. Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, et al. Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice. Am J Physiol Renal Physiol. 2008; 294:F264–F271.

110. Wu H, Chen G, Wyburn KR, Yin J, Bertolino P, Eris JM, et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest. 2007; 117:2847–2859.

111. Wolfs TG, Buurman WA, van Schadewijk A, de Vries B, Daemen MA, Hiemstra PS, et al. In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol. 2002; 168:1286–1293.

112. Kim BS, Lim SW, Li C, Kim JS, Sun BK, Ahn KO, et al. Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation. 2005; 79:1370–1377.

113. Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest. 2005; 115:2894–2903.