Skip to main content
SpringerLink
Log in

Role of Complement Activation in Allograft Inflammation

  • Immunology (R Fairchild, Section Editor)
  • Published:
Current Transplantation Reports Aims and scope Submit manuscript

Abstract

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.

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  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.

    Article  CAS  PubMed  Google Scholar 

  2. Cravedi P, Heeger PS. Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest. 2014;124(6):2348–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mathern DR, Heeger PS. Molecules great and small: the complement system. Clin J Am Soc Nephrol. 2015;10(9):1636–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gorsuch WB, Chrysanthou E, Schwaeble WJ, Stahl GL. The complement system in ischemia-reperfusion injuries. Immunobiology. 2012;217(11):1026–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ponticelli C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol Dial Transplant. 2014;29(6):1134–40.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lublin DM, Atkinson JP. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu Rev Immunol. 1989;7:35–58.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

  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. https://doi.org/10.1111/ajt.15222.

  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.

  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.

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sheen JH, Heeger PS. Effects of complement activation on allograft injury. Curr Opin Organ Transplant. 2015;20(4):468–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  42. Ochando J, Conde P, Bronte V. Monocyte-derived suppressor cells in transplantation. Curr Transplant Rep. 2015;2(2):176–83.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/ajt.15072.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  58. Thurman JM, Le Quintrec M. Targeting the complement cascade: novel treatments coming down the pike. Kidney Int. 2016;90(4):746–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

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

Author information

Authors and Affiliations

  1. Translational Transplant Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Nicholas H. Chun, Julian K. Horwitz & Peter S. Heeger

  2. Division of Nephrology in the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Nicholas H. Chun & Peter S. Heeger

  3. The Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Julian K. Horwitz & Peter S. Heeger

Authors
  1. Nicholas H. Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julian K. Horwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter S. Heeger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter S. Heeger.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Immunology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chun, N.H., Horwitz, J.K. & Heeger, P.S. Role of Complement Activation in Allograft Inflammation. Curr Transpl Rep 6, 52–59 (2019). https://doi.org/10.1007/s40472-019-0224-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40472-019-0224-2

Keywords

Search

Navigation