Role of Complement Activation in Allograft Inflammation

  • Nicholas H. Chun
  • Julian K. Horwitz
  • Peter S. HeegerEmail author
Immunology (R Fairchild, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Immunology


Purpose of Review

Novel paradigms have broadened our understanding of mechanisms through which complement mediates allograft inflammation/injury. Herein, we review advances in the field and highlight therapeutic implications.

Recent Findings

Pre-clinical and translational human trials have elucidated complement-dependent mechanisms of post-transplant ischemia-reperfusion (I/R) injury. Immune cell-derived, and intracellular, complement activation is newly linked to proinflammatory T cell immunity relevant to allograft rejection. Complement-induced immune regulation, including C5a ligation of C5a receptor 2 on T cells, C5a/C5a receptor 1 interactions on regulatory myeloid cells, and C1q binding to CD8+ T cells, can inhibit proinflammatory T cells and/or prolong murine allograft survival. Pilot trials of complement inhibition to treat/prevent human I/R- or antibody-initiated allograft injury show promise.


The complement system participates in allograft injury through multiple context-dependent mechanisms involving various components and receptors. These new insights along with development and implementation of individualized complement inhibitory strategies have potential to improve transplant outcomes.


Complement T cell activation Ischemia reperfusion injury Allograft inflammation Antibody-mediated rejection 



The work was supported by NIH grants R01 AI071185 and AI132405 awarded to PSH and K08 AI135101 to NC.

Compliance with Ethical Standards

Conflict of Interest

Peter Heeger reports grants from Alexion and serves on the Chemocentryx scientific advisory board. Nicholas Chun reports grants from NIAID during the conduct of the study. Julian Horwitz declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Cravedi P, Leventhal J, Lakhani P, Ward SC, Donovan MJ, Heeger PS. Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant. 2013;13(10):2530–9 Study showing complement regulation of T cell immunity is operant in human cells. PubMedCrossRefGoogle Scholar
  2. 2.
    Cravedi P, Heeger PS. Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest. 2014;124(6):2348–54.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mathern DR, Heeger PS. Molecules great and small: the complement system. Clin J Am Soc Nephrol. 2015;10(9):1636–50.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Arnold JN, Dwek RA, Rudd PM, Sim RB. Mannan binding lectin and its interaction with immunoglobulins in health and in disease. Immunol Lett. 2006;106(2):103–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang M, Takahashi K, Alicot EM, Vorup-Jensen T, Kessler B, Thiel S, et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J Immunol. 2006;177(7):4727–34.PubMedCrossRefGoogle Scholar
  6. 6.
    • Jane-Wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, et al. Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-κB signaling in endothelial cells. Circulation. 2013;128(23):2504–16 Complement-induced activation of allograft endothelial cells via nuclear factor-κB signaling. Google Scholar
  7. 7.
    Kwan WH, van der Touw W, Paz-Artal E, Li MO, Heeger PS. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med. 2013;210(2):257–68.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Gorsuch WB, Chrysanthou E, Schwaeble WJ, Stahl GL. The complement system in ischemia-reperfusion injuries. Immunobiology. 2012;217(11):1026–33.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ponticelli C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol Dial Transplant. 2014;29(6):1134–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Sommer W, Tudorache I, Kuhn C, Avsar M, Salman J, Ius F, et al. C1-esterase-inhibitor for primary graft dysfunction in lung transplantation. Transplantation. 2014;97(11):1185–91.PubMedCrossRefGoogle Scholar
  11. 11.
    • Atkinson C, Qiao F, Yang X, Zhu P, Reaves N, Kulik L, et al. Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury. Circulation. 2015;131(13):1171–80 Description of preformed antibodies as pathogenic mediators of transplant associated ischemia reperfusion injury. PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    • Chun N, Fairchild RL, Li Y, Liu J, Zhang M, Baldwin WM, et al. Complement dependence of murine costimulatory blockade-resistant cellular cardiac allograft rejection. Am J Transplant. 2017;17(11):2810–9 Shows recipient mannose-binding lectin pathway initiated recipient complement activation as a mediator of cardiac allograft ischemia reperfusion injury and late graft loss. PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    • Farrar CA, Tran D, Li K, Wu W, Peng Q, Schwaeble W, et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J Clin Invest. 2016;126(5):1911–25 Identification of allograft-derived collectin-11 as an initiator of pathogenic complement activation and renal allograft ischemia reperfusion injury. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Peng Q, Li K, Smyth LA, Xing G, Wang N, Meader L, et al. C3a and C5a promote renal ischemia-reperfusion injury. J Am Soc Nephrol. 2012;23(9):1474–85.Google Scholar
  15. 15.
    Lalli PN, Zhou W, Sacks S, Medof ME, Heeger PS. Locally produced and activated complement as a mediator of alloreactive T cells. Front Biosci (Schol Ed). 2009;1:117–24.CrossRefGoogle Scholar
  16. 16.
    • Jordan SC, Choi J, Aubert O, Haas M, Loupy A, Huang E, et al. A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients. Am J Transplant. 2018;18(12):2955–64 Translational human trial showing promise of C1-inhibitor therapy for improving outcomes in kidney transplant recipients of organs at risk for delayed graft function. PubMedCrossRefGoogle Scholar
  17. 17.
    Heeger P, Akalin E, Baweja M, Bloom R, Florman S, Haydel B, et al. Lack of efficacy of eculizumab for prevention of delayed graft function (DGF) in deceased donor kidney transplant recipients. Am J Transplant. 2018;18(S4):674.Google Scholar
  18. 18.
    Cheng Q, Patel K, Lei B, Rucker L, Allen DP, Zhu P, et al. Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant. Am J Transplant. 2018;18:2417–28.Google Scholar
  19. 19.
    Patel H, Smith RA, Sacks SH, Zhou W. Therapeutic strategy with a membrane-localizing complement regulator to increase the number of usable donor organs after prolonged cold storage. J Am Soc Nephrol. 2006;17(4):1102–11.PubMedCrossRefGoogle Scholar
  20. 20.
    Xiao F, Ma L, Zhao M, Smith RA, Huang G, Jones PM, et al. APT070 (mirococept), a membrane-localizing C3 convertase inhibitor, attenuates early human islet allograft damage in vitro and in vivo in a humanized mouse model. Br J Pharmacol. 2016;173(3):575–87.Google Scholar
  21. 21.
    Kassimatis T, Qasem A, Douiri A, Ryan EG, Rebollo-Mesa I, Nichols LL, et al. A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial. Trials. 2017;18(1):255.Google Scholar
  22. 22.
    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(12):5921–5.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Lublin DM, Atkinson JP. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol. 1989;7:35–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Pavlov V, Raedler H, Yuan S, Leisman S, Kwan WH, Lalli PN, et al. Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection. J Immunol. 2008;181(7):4580–9.Google Scholar
  25. 25.
    Raedler H, Vieyra MB, Leisman S, Lakhani P, Kwan W, Yang M, et al. Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice. Am J Transplant. 2011;11(7):1397–406.Google Scholar
  26. 26.
    Gueler F, Rong S, Gwinner W, Mengel M, Brocker V, Schon S, et al. Complement 5a receptor inhibition improves renal allograft survival. J Am Soc Nephrol. 2008;19(12):2302–12.Google Scholar
  27. 27.
    Mathern DR, Horwitz JK, Heeger PS. Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8+ T cell immunity and prolongs murine cardiac allograft survival. Am J Transplant. 2018.
  28. 28.
    Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N, et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity. 2008;28(3):425–35.Google Scholar
  29. 29.
    Sheen JH, Strainic MG, Liu J, Zhang W, Yi Z, Medof ME, et al. TLR-induced murine dendritic cell (DC) activation requires DC-intrinsic complement. J Immunol. 2017;199(1):278–91.Google Scholar
  30. 30.
    Li K, Fazekasova H, Wang N, Sagoo P, Peng Q, Khamri W, et al. Expression of complement components, receptors and regulators by human dendritic cells. Mol Immunol. 2011;48(9–10):1121–7.Google Scholar
  31. 31.
    •• Arbore G, West EE, Spolski R, Robertson AAB, Klos A, Rheinheimer C, et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science. 2016;352(6292):aad1210 Novel mechanism describing requisite complement-induced, T cell-intrinsic, inflammasome activation for development of Th1 immunity in human CD4+ T cells. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Sheen JH, Heeger PS. Effects of complement activation on allograft injury. Curr Opin Organ Transplant. 2015;20(4):468–75.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol. 2013;14(2):162–71.PubMedCrossRefGoogle Scholar
  34. 34.
    Okinaga S, Slattery D, Humbles A, Zsengeller Z, Morteau O, Kinrade MB, et al. C5L2, a nonsignaling C5A binding protein. Biochemistry. 2003;42(31):9406–15.Google Scholar
  35. 35.
    Verghese AD, Demir M, Chun N, Fribourg M, Cravedi P, Llaudo I, et al. T cell expression of C5a receptor 2 augments murine regulatory T cell (T). J Immunol. 2018;200(6):2186–98.CrossRefGoogle Scholar
  36. 36.
    Croker DE, Monk PN, Halai R, Kaeslin G, Schofield Z, Wu MC, et al. Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunol Cell Biol. 2016;94(8):787–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Karsten CM, Wiese AV, Mey F, Figge J, Woodruff TM, Reuter T, et al. Monitoring C5aR2 expression using a Floxed tdTomato-C5aR2 Knock-in mouse. J Immunol. 2017;199(9):3234–48.Google Scholar
  38. 38.
    Pundir P, MacDonald CA, Kulka M. The novel receptor C5aR2 is required for C5a-mediated human mast cell adhesion, migration, and proinflammatory mediator production. J Immunol. 2015;195(6):2774–87.PubMedCrossRefGoogle Scholar
  39. 39.
    Gerard NP, Lu B, Liu P, Craig S, Fujiwara Y, Okinaga S, et al. An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J Biol Chem. 2005;280(48):39677–80.Google Scholar
  40. 40.
    Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C, et al. Modulation of the antitumor immune response by complement. Nat Immunol. 2008;9(11):1225–35.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ajona D, Ortiz-Espinosa S, Moreno H, Lozano T, Pajares MJ, Agorreta J, et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 2017;7(7):694–703.Google Scholar
  42. 42.
    Ochando J, Conde P, Bronte V. Monocyte-derived suppressor cells in transplantation. Curr Transplant Rep. 2015;2(2):176–83.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Llaudo I, Fribourg M, Edward Medof M, Conde P, Ochando J, Heeger PS. C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival. Am J Transplant. 2018.
  44. 44.
    •• Ling GS, Crawford G, Buang N, Bartok I, Tian K, Thielens NM, et al. C1q restrains autoimmunity and viral infection by regulating CD8. Science. 2018;360(6388):558–63 New paradigm of T cell regulation by C1q-mediated metabolic reprogramming. PubMedCrossRefGoogle Scholar
  45. 45.
    Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460(7251):103–7.Google Scholar
  46. 46.
    van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev. 2012;249(1):27–42.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Fang Y, Xu C, Fu YX, Holers VM, Molina H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J Immunol. 1998;160(11):5273–9.PubMedGoogle Scholar
  48. 48.
    Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271(5247):348–50.PubMedCrossRefGoogle Scholar
  49. 49.
    Marsh JE, Farmer CK, Jurcevic S, Wang Y, Carroll MC, Sacks SH. The allogeneic T and B cell response is strongly dependent on complement components C3 and C4. Transplantation. 2001;72(7):1310–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Wang H, Arp J, Liu W, Faas SJ, Jiang J, Gies DR, et al. Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation. J Immunol. 2007;179(7):4451–63.Google Scholar
  51. 51.
    Valenzuela NM, McNamara JT, Reed EF. Antibody-mediated graft injury: complement-dependent and complement-independent mechanisms. Curr Opin Organ Transplant. 2014;19(1):33–40.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol. 2012;8(11):670–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011;11(11):2405–13.Google Scholar
  54. 54.
    Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, et al. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009;9(1):231–5.Google Scholar
  55. 55.
    Burbach M, Suberbielle C, Brochériou I, Ridel C, Mesnard L, Dahan K, et al. Report of the inefficacy of eculizumab in two cases of severe antibody-mediated rejection of renal grafts. Transplantation. 2014;98(10):1056–9.Google Scholar
  56. 56.
    Montgomery RA, Orandi BJ, Racusen L, Jackson AM, Garonzik-Wang JM, Shah T, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am J Transplant. 2016;16(12):3468–78.Google Scholar
  57. 57.
    • Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 2015;99(2):299–308 Pilot clinical study showing safety and potential efficacy of C1INH therapy for prevention of antibody-mediated rejection in high risk transplant recipients. PubMedCrossRefGoogle Scholar
  58. 58.
    Thurman JM, Le Quintrec M. Targeting the complement cascade: novel treatments coming down the pike. Kidney Int. 2016;90(4):746–52.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicholas H. Chun
    • 1
    • 2
  • Julian K. Horwitz
    • 1
    • 3
  • Peter S. Heeger
    • 1
    • 2
    • 3
    Email author
  1. 1.Translational Transplant Research Center, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Division of Nephrology in the Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.The Precision Institute of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkUSA

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