Role of Complement Activation in Allograft Inflammation
- 30 Downloads
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.
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.
KeywordsComplement 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
- 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
- 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.• 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.• 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.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
- 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.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.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
- 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.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
- 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.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.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.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.Google Scholar
- 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.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.•• 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
- 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
- 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
- 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
- 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
- 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.
- 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
- 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
- 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.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.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.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.• 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