Abstract
Graft loss to rejection remains a key impediment to transplant success, which limits the therapeutic potential of this procedure. Though adaptive immune cells are critical in rejection, recent studies have demonstrated the importance of innate immune cells in dictating transplant outcomes (rejection or survival), highlighting the necessity in therapeutically targeting innate immune cells in the induction of tolerance to organ transplants. However, there are many challenges facing the field, as innate immune system consists of diverse cell types, molecular sensors, and soluble mediators that are different from those in the adaptive system. Also, some innate immune cells mediate graft injury, while others promote transplant survival, making therapeutic targeting of innate immune cells a challenging task. In this chapter, key elements in the innate immune system, their responses to organ transplants, as well as the challenges and opportunities in targeting those elements in favor of transplant survival are reviewed.
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Murphy SP, Porrett PM, Turka LA (2011) Innate immunity in transplant tolerance and rejection. Immunol Rev 241(1):39–48
Liu W, Li XC (2010) An overview on non-T cell pathways in transplant rejection and tolerance. Curr Opin Organ Transplant 15(4):422–426
LaRosa DF, Rahman AH, Turka LA (2007) The innate immune system in allograft rejection and tolerance. J Immunol 178(12):7503–7509
Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11(5):373–384
Elinav E, Strowig T, Henao-Mejia J et al (2011) Regulation of the antimicrobial response by NLR proteins. Immunity 34(5):665–679
Kato H, Takahasi K, Fujita T (2011) RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol Rev 243(1):91–98
O'Neill LAJ, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7(5):353–364
Cao X (2015) Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16(1):35–50
Zipfel PF, Skerka C (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9(10):729–740
Cravedi P, Heeger PS (2014) Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest 124(6):2348–2354
Medof ME, Kinoshita T, Nussenzweig V (1984) Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med 160(5):1558–1578
Chen Song S, Zhong S, Xiang Y et al (2011) Complement inhibition enables renal allograft accommodation and long-term engraftment in presensitized nonhuman primates. Am J Transplant 11(10):2057–2066
Blom AM, Villoutreix BO, Dahlback B (2004) Complement inhibitor C4b-binding protein-friend or foe in the innate immune system? Mol Immunol 40(18):1333–1346
Collard CD, Bukusoglu C, Agah A et al (1999) Hypoxia-induced expression of complement receptor type 1 (CR1, CD35) in human vascular endothelial cells. Am J Physiol 276(2 Pt 1):C450–C458
Ollert MW, David K, Bredehorst R et al (1995) Classical complement pathway activation on nucleated cells. Role of factor H in the control of deposited C3b. J Immunol 155(10):4955–4962
Heeger PS, Lalli PN, Lin F et al (2005) Decay-accelerating factor modulates induction of T cell immunity. J Exp Med 201(10):1523–1530
Lalli PN, Strainic MG, Yang M et al (2008) Locally produced C5a binds to T cell expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112(5):1759–1766
Cravedi P, van der Touw W, Heeger PS (2013) Complement regulation of T-cell alloimmunity. Semin Nephrol 33(6):565–574
Castellano G, Woltman AM, Nauta AJ et al (2004) Maturation of dendritic cells abrogates C1q production in vivo and in vitro. Blood 103(10):3813–3820
Strainic MG, Liu J, Huang D et al (2008) Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28(3):425–435
Pratt JR, Basheer SA, Sacks SH (2002) Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 8(6):582–587
Shi FD, Ljunggren HG, La Cava A et al (2011) Organ-specific features of natural killer cells. Nat Rev Immunol 11(10):658–671
Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274
Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9(5):495–502
Elliott JM, Yokoyama WM (2011) Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol 32(8):364–372
Ruggeri L, Capanni M, Urbani E et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562):2097–2100
Yu G, Xu X, Vu MD et al (2006) NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med 203(8):1851–1858
Kroemer A, Edtinger K, Li XC (2008) The innate NK cells in transplant rejection and tolerance induction. Curr Opin Organ Transplant 13:339–343
Sun JC (2010) Re-educating natural killer cells. J Exp Med 207(10):2049–2052
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964
Auffray C, Fogg D, Garfa M et al (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317(5838):666–670
Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737
Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11(10):889–896
Denning TL, Wang YC, Patel SR et al (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8(10):1086–1094
Brem-Exner BG, Sattler C, Hutchinson JA et al (2008) Macrophages driven to a novel state of activation have anti-inflammatory properties in mice. J Immunol 180(1):335–349
Allavena P, Sica A, Garlanda C et al (2008) The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev 222(1):155–161
Liu W, Xiao X, Demirci G et al (2012) Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms. J Immunol 188(6):2703–2711
Fox A, Mountford J, Braakhuis A et al (2001) Innate and adaptive immune responses to nonvascular xenografts: evidence that macrophages are direct effectors of xenograft rejection. J Immunol 166(3):2133–2140
Coquerelle C, Moser M (2010) DC subsets in positive and negative regulation of immunity. Immunol Rev 234(1):317–334
Ueno H, Schmitt N, Klechevsky E et al (2010) Harnessing human dendritic cell subsets for medicine. Immunol Rev 234(1):199–212
Morelli AE, Thomson AW (2007) Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7:610–621
Manicassamy S, Pulendran B (2011) Dendritic cell control of tolerogenic responses. Immunol Rev 241(1):206–227
Ohnmacht C, Pullner A, King SBS et al (2009) Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 206(3):549–559
Grommes J, Soehnlein O (2011) Contribution of neutrophils to acute lung injury. Mol Med 17(3–4):293–307
Fialkow L, Wang Y, Downey GP (2007) Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med 42(2):153–164
El-Sawy T, Belperio JA, Strieter RM et al (2005) Inhibition of polymorphonuclear leukocyte-mediated graft damage synergizes with short-term costimulatory blockade to prevent cardiac allograft rejection. Circulation 112(3):320–331
Suurmond J, van Heemst J, van Heiningen J et al (2013) Communication between human mast cells and CD4(+) T cells through antigen-dependent interactions. Eur J Immunol 43(7):1758–1768
de Vries VC, Wasiuk A, Bennett KA et al (2009) Mast cell degranulation breaks peripheral tolerance. Am J Transplant 9(10):2270–2280
Lu LF, Lind EF, Gondek DC et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442(7106):997–1002
Talayero P, Mancebo E, Calvo-Pulido J et al (2016) Innate lymphoid cells groups 1 and 3 in the epithelial compartment of functional human intestinal allografts. Am J Transplant 16(1):72–82
Konya V, Mjosberg J (2015) Innate lymphoid cells in graft-versus-host disease. Am J Transplant 15(11):2795–2801
Taniguchi M, Harada M, Kojo S et al (2003) The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol 21:483–513
Ikehara Y, Yasunami Y, Kodama S et al (2000) CD4(+) Valpha14 natural killer T cells are essential for acceptance of rat islet xenografts in mice. J Clin Invest 105(12):1761–1767
Seino KI, Fukao K, Muramoto K et al (2001) Requirement for natural killer T (NKT) cells in the induction of allograft tolerance. Proc Natl Acad Sci U S A 98(5):2577–2581
Shigeoka AA, Holscher TD, King AJ et al (2007) TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both myD88-dependent and -independent pathways. J Immunol 178(10):6252–6258
Zhai Y, Shen XD, O'Connell R et al (2004) Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 173(12):7115–7119
Chong AJ, Shimamoto A, Hampton CR et al (2004) Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128(2):170–179
Li L, Okusa MD (2010) Macrophages, dendritic cells, and kidney ischemia-reperfusion injury. Semin Nephrol 30(3):268–277
Zhang ZX, Wang S, Huang X et al (2008) NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemia-reperfusion injury. J Immunol 181(11):7489–7498
Ysebaert DK, De Greef KE, Vercauteren SR et al (2000) Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 15(10):1562–1574
Huen SC, Cantley LG (2015) Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol 30(2):199–209
Maroko PR, Carpenter CB, Chiariello M et al (1978) Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion. J Clin Invest 61(3):661–670
Diepenhorst GMP, Van Gulik TM, Hack CE (2009) Complement-mediated ischemia-reperfusion injury: Lessons learned from animal and clinical studies. Ann Surg 249(6):889–899
Brown KM, Kondeatis E, Vaughan RW et al (2006) Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 354(19):2014–2023
Zhou W, Farrar CA, Abe K et al (2000) Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 105(10):1363–1371
Yamada K, Miwa T, Liu J et al (2004) Critical protection from renal ischemia reperfusion injury by CD55 and CD59. J Immunol 172(6):3869–3875
Lu X, Li Y, Simovic MO et al (2011) Decay-accelerating factor attenuates c-reactive protein-potentiated tissue injury after mesenteric ischemia/reperfusion. J Surg Res 167(2):e103–e115
Zhou W, Medof ME, Heeger PS et al (2007) Graft-derived complement as a mediator of transplant injury. Curr Opin Immunol 19(5):569–576
Farrar CA, Zhou W, Lin T et al (2006) Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J 20(2):217–226
Pratt JR, Jones ME, Dong J et al (2003) Nontransgenic hyperexpression of a complement regulator in donor kidney modulates transplant ischemia/reperfusion damage, acute rejection, and chronic nephropathy. Am J Pathol 163(4):1457–1465
Oberbarnscheidt MH, Zeng Q, Li Q et al (2014) Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 124(8):3579–3589
Li XC, Rothstein DM, Sayegh MH (2009) Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 229:271–293
Goldstein DR, Tesar BM, Akira S et al (2003) Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest 111(10):1571–1578
McKay D, Shigeoka A, Rubinstein M et al (2006) Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection. Eur J Immunol 36(8):1994–2002
Hancock WW, Thomson NM, Atkins RC (1983) Composition of interstitial cellular infiltrate identified by monoclonal antibodies in renal biopsies of rejecting human renal allografts. Transplantation 35:458–463
Matheson PJ, Dittmer ID, Beaumont BW et al (2005) The macrophage is the predominant inflammatory cell in renal allograft intimal arteritis. Transplantation 79(12):1658–1662
Gao W, Topham PS, King JA et al (2000) Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest 105(1):35–44
Jose MD, Ikezumi Y, Van Rooijen N et al (2003) Macrophages act as effectors of tissue damage in acute renal allograft rejection. Transplantation 76(7):1015–1022
Qi F, Adair A, Ferenbach D et al (2008) Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation. Transplantation 86(9):1267–1274
Kirk AD, Hale DA, Mannon RB et al (2003) Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (Campath-1H). Transplantation 76(1):120–129
Kaul AM, Goparaju S, Dvorina N et al (2015) Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants. Am J Transplant 15(2):333–345
Wu T, Bond G, Martin D et al (2006) Histopathologic characteristics of human intestine allograft acute rejection in patients pretreated with thymoglobulin or alemtuzumab. Am J Gastroenterol 101(7):1617–1624
Kim J, Chang CK, Hayden T et al (2007) The activating immunoreceptor NKG2D and its ligands are involved in allograft transplant rejection. J Immunol 179(10):6416–6420
Degli-Esposti MA, Smyth MJ (2005) Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol 5:112–124
Kroemer A, Xiao X, Degauque N et al (2008) The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol 180(12):7818–7826
Martin-Fontecha A, Thomsen LL, Brett S et al (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5(12):1260–1265
Colvin RB (2007) Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 18(4):1046–1056
Fuquay R, Renner B, Kulik L et al (2013) Renal ischemia-reperfusion injury amplifies the humoral immune response. J Am Soc Nephrol 24(7):1063–1072
Raedler H, Heeger PS (2011) Complement regulation of T-cell alloimmunity. Curr Opin Organ Transplant 16(1):54–60
Pavlov V, Raedler H, Yuan S et al (2008) Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection. J Immunol 181(7):4580–4589
Solez K, Colvin RB, Racusen LC et al (2008) Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 8(4):753–760
Racusen LC, Regele H (2010) The pathology of chronic allograft dysfunction. Kidney Int 78(suppl 119):S27–S32
Michelsen KS, Doherty TM, Shah PK et al (2004) TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol 173(10):5901–5907
Mann DL (2011) The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res 108(9):1133–1145
Wang S, Schmaderer C, Kiss E et al (2010) Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis Model Mech 3(1–2):92–103
Methe H, Zimmer E, Grimm C et al (2004) Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation. Transplantation 78(9):1324–1331
Kitchens WH, Chase CM, Uehara S et al (2007) Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant 7:2675–2682
Yang J, Reutzel-Selke A, Steier C et al (2003) Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-(gamma) accelerates chronic graft injury in a rat renal allograft model. J Am Soc Nephrol 14(1):214–225
Ricardo SD, Van Goor H, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118(11):3522–3530
Niedermeier M, Reich B, Gomez MR et al (2009) CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A 106(42):17892–17897
Pilmore HL, Painter DM, Bishop GA et al (2000) Early up-regulation of macrophages and myofibroblasts: a new marker for development of chronic renal allograft rejection. Transplantation 69(12):2658–2662
Jevnikar AM, Mannon RB (2008) Late kidney allograft loss: what we know about it, and what we can do about it. Clin J Am Soc Nephrol 3(Suppl 2):S56–S67
Toki D, Zhang W, Hor KL et al (2014) The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation. Am J Transplant 14(9):2126–2136
Ikezumi Y, Suzuki T, Yamada T et al (2015) Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury. Pediatr Nephrol 30(6):1007–1017
Einecke G, Sis B, Reeve J et al (2009) Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant 9(11):2520–2531
Gaston RS, Cecka JM, Kasiske BL et al (2010) Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation 90(1):68–74
Qian Z, Hu W, Liu J et al (2001) Accelerated graft arteriosclerosis in cardiac transplants. Transplantation 72(5):900–906
Sheerin NS, Risley P, Abe K et al (2008) Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury. FASEB J 22(4):1065–1072
Hirohashi T, Chase CM, Della Pelle P et al (2012) A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant 12(2):313–321
Sis B, Campbell PM, Mueller T et al (2007) Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 7(7):1743–1752
Van Bergen J, Thompson A, Haasnoot GW et al (2011) KIR-ligand mismatches are associated with reduced long-term graft survival in HLA-compatible kidney transplantation. Am J Transplant 11(9):1959–1964
Uehara S, Chase CM, Kitchens WH et al (2005) NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts. J Immunol 175(5):3424–3430
Li XC, Strom TB, Turka LA et al (2001) T cell death and transplantation tolerance. Immunity 14:407–416
Schulz O, Reis E, Sousa C (2002) Cross-presentation of cell-associated antigens by CD8(alpha)+ dendritic cells is attributable to their ability to internalize dead cells. Immunology 107(2):183–189
Iyoda T, Shimoyama S, Liu K et al (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195(10):1289–1302
Schnorrer P, Behrens GMN, Wilson NS et al (2006) The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proc Natl Acad Sci U S A 103(28):10729–10734
Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407(6805):784–788
Morelli AE, Larregina AT (2010) Apoptotic cell-based therapies against transplant rejection: role of recipient's dendritic cells. Apoptosis 15(9):1083–1097
Mueller DL, Jenkins MK, Schwartz RH (1989) Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 7:445–480
Hill M, Thebault P, Segovia M et al (2011) Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and Epstein-Barr virus-induced gene 3. Am J Transplant 11(10):2036–2045
Hutchinson JA, Riquelme P, Sawitzki B et al (2011) Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 187(5):2072–2078
Bezie S, Picarda E, Ossart J et al (2015) IL-34 is a Treg-specific cytokine and mediates transplant tolerance. J Clin Invest 125(10):3952–3964
Conde P, Rodriguez M, van der Touw W et al (2015) DC-SIGN(+) macrophages control the induction of transplantation tolerance. Immunity 42(6):1143–1158
Deniz G, Erten G, Kucuksezer UC et al (2008) Regulatory NK cells suppress antigen-specific T cell responses. J Immunol 180(2):850–857
van der Touw W, Burrell B, Lal G et al (2012) NK cells are required for costimulatory blockade induced tolerance to vascularized allografts. Transplantation 94(6):575–584
Adams AB, Williams MA, Jones TR et al (2003) Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 111(12):1887–1895
Porrett PM, Yuan X, LaRosa DF et al (2008) Mechanisms underlying blockade of allograft acceptance by TLR ligands. J Immunol 181(3):1692–1699
Walker WE, Nasr IW, Camirand G et al (2006) Absence of innate MyD88 signaling promotes inducible allograft acceptance. J Immunol 177(8):5307–5316
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Zhao, Y., Lan, P., Li, X.C. (2017). Modulation of Innate Immune Cells to Create Transplant Tolerance. In: Corradetti, B. (eds) The Immune Response to Implanted Materials and Devices. Springer, Cham. https://doi.org/10.1007/978-3-319-45433-7_7
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