Advertisement
Review Article| Volume 39, ISSUE 1, P31-43, March 2019

Complement and Transplantation

From New Mechanisms to Potential Biomarkers and Novel Treatment Strategies
  • Julian K. Horwitz
    Affiliations
    Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA

    Department of Surgery, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Nicholas H. Chun
    Affiliations
    Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA

    Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Peter S. Heeger
    Correspondence
    Corresponding author. Translational Transplant Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, Annenberg Building Box 1243, One Gustave L Levy Place, New York, NY 10029.
    Affiliations
    Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA

    Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA

    The Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY 10029, USA
    Search for articles by this author
Published:December 19, 2018DOI:https://doi.org/10.1016/j.cll.2018.10.004

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Walport M.J.
        Complement. First of two parts.
        N Engl J Med. 2001; 344: 1058-1066
        • Takahashi K.
        • Ip W.E.
        • Michelow I.C.
        • et al.
        The mannose-binding lectin: a prototypic pattern recognition molecule.
        Curr Opin Immunol. 2006; 18: 16-23
        • Bamberg C.E.
        • Mackay C.R.
        • Lee H.
        • et al.
        The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction.
        J Biol Chem. 2010; 285: 7633-7644
        • Park P.
        • Haas M.
        • Cunningham P.N.
        • et al.
        Inhibiting the complement system does not reduce injury in renal ischemia reperfusion.
        J Am Soc Nephrol. 2001; 12: 1383-1390
        • Adler S.
        • Baker P.J.
        • Johnson R.J.
        • et al.
        Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells.
        J Clin Invest. 1986; 77: 762-767
        • Ricklin D.
        • Hajishengallis G.
        • Yang K.
        • et al.
        Complement: a key system for immune surveillance and homeostasis.
        Nat Immunol. 2010; 11: 785-797
        • Guo R.F.
        • Ward P.A.
        Role of C5a in inflammatory responses.
        Annu Rev Immunol. 2005; 23: 821-852
        • Klos A.
        • Tenner A.J.
        • Johswich K.O.
        • et al.
        The role of the anaphylatoxins in health and disease.
        Mol Immunol. 2009; 46: 2753-2766
        • Kwan W.H.
        • van der Touw W.
        • Paz-Artal E.
        • et al.
        Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells.
        J Exp Med. 2013; 210: 257-268
        • van der Touw W.
        • Cravedi P.
        • Kwan W.H.
        • et al.
        Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells.
        J Immunol. 2013; 190: 5921-5925
        • Peake P.W.
        • O'Grady S.
        • Pussell B.A.
        • et al.
        C3a is made by proximal tubular HK-2 cells and activates them via the C3a receptor.
        Kidney Int. 1999; 56: 1729-1736
        • Lalli P.N.
        • Strainic M.G.
        • Yang M.
        • et al.
        Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis.
        Blood. 2008; 112: 1759-1766
        • Siedlecki A.
        • Irish W.
        • Brennan D.C.
        Delayed graft function in the kidney transplant.
        Am J Transplant. 2011; 11: 2279-2296
        • Zhang M.
        • Carroll M.C.
        Natural IgM-mediated innate autoimmunity: a new target for early intervention of ischemia-reperfusion injury.
        Expert Opin Biol Ther. 2007; 7: 1575-1582
        • Haas M.S.
        • Alicot E.M.
        • Schuerpf F.
        • et al.
        Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction.
        Cardiovasc Res. 2010; 87: 618-627
        • Busche M.N.
        • Pavlov V.
        • Takahashi K.
        • et al.
        Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin.
        Am J Physiol Heart Circ Physiol. 2009; 297: H1853-H1859
        • Nauser C.L.
        • Farrar C.A.
        • Sacks S.H.
        Complement recognition pathways in renal transplantation.
        J Am Soc Nephrol. 2017; 28: 2571-2578
        • Thurman J.M.
        • Ljubanovic D.
        • Edelstein C.L.
        • et al.
        Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice.
        J Immunol. 2003; 170: 1517-1523
        • De Vries B.
        • Matthijsen R.A.
        • Wolfs T.G.
        • et al.
        Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation.
        Transplantation. 2003; 75: 375-382
        • Peng Q.
        • Li K.
        • Smyth L.A.
        • et al.
        C3a and C5a promote renal ischemia-reperfusion injury.
        J Am Soc Nephrol. 2012; 23: 1474-1485
        • Farrar C.A.
        • Zhou W.
        • Lin T.
        • et al.
        Local extravascular pool of C3 is a determinant of postischemic acute renal failure.
        FASEB J. 2006; 20: 217-226
        • Atkinson C.
        • Floerchinger B.
        • Qiao F.
        • et al.
        Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts.
        Circulation. 2013; 127: 1290-1299
        • Chun N.
        • Fairchild R.L.
        • Li Y.
        • et al.
        Complement dependence of murine costimulatory blockade-resistant cellular cardiac allograft rejection.
        Am J Transplant. 2017; 17: 2810-2819
        • Jordan S.C.
        • Choi J.
        • Aubert O.
        • 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; https://doi.org/10.1111/ajt.14767
        • Sommer W.
        • Tudorache I.
        • Kuhn C.
        • et al.
        C1-esterase-inhibitor for primary graft dysfunction in lung transplantation.
        Transplantation. 2014; 97: 1185-1191
        • Cheng Q.
        • Patel K.
        • Lei B.
        • et al.
        Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant.
        Am J Transplant. 2018; 18: 2417-2428
        • Patel H.
        • Smith R.A.
        • Sacks S.H.
        • et al.
        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: 1102-1111
        • Xiao F.
        • Ma L.
        • Zhao M.
        • 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: 575-587
        • Kassimatis T.
        • Qasem A.
        • Douiri A.
        • 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: 255
        • Heeger P.
        • Akalin E.
        • Baweja M.
        • 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: 674
        • Pratt J.R.
        • Basheer S.A.
        • Sacks S.H.
        Local synthesis of complement component C3 regulates acute renal transplant rejection.
        Nat Med. 2002; 8: 582-587
        • Strainic M.G.
        • Liu J.
        • Huang D.
        • et al.
        Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells.
        Immunity. 2008; 28: 425-435
        • Sheen J.H.
        • Strainic M.G.
        • Liu J.
        • et al.
        TLR-induced murine dendritic cell (DC) activation requires DC-intrinsic complement.
        J Immunol. 2017; 199: 278-291
        • Cravedi P.
        • Leventhal J.
        • Lakhani P.
        • et al.
        Immune cell-derived C3a and C5a costimulate human T cell alloimmunity.
        Am J Transplant. 2013; 13: 2530-2539
        • Li K.
        • Fazekasova H.
        • Wang N.
        • et al.
        Expression of complement components, receptors and regulators by human dendritic cells.
        Mol Immunol. 2011; 48: 1121-1127
        • Liszewski M.K.
        • Kolev M.
        • Le Friec G.
        • et al.
        Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation.
        Immunity. 2013; 39: 1143-1157
        • Ghannam A.
        • Fauquert J.L.
        • Thomas C.
        • et al.
        Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation.
        Mol Immunol. 2014; 58: 98-107
        • Strainic M.G.
        • Shevach E.M.
        • An F.
        • et al.
        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: 162-171
        • Okinaga S.
        • Slattery D.
        • Humbles A.
        • et al.
        C5L2, a nonsignaling C5A binding protein.
        Biochemistry. 2003; 42: 9406-9415
        • Verghese D.A.
        • Demir M.
        • Chun N.
        • et al.
        T cell expression of C5a receptor 2 augments murine regulatory T cell (TREG) generation and TREG-dependent cardiac allograft survival.
        J Immunol. 2018; 200: 2186-2198
        • Stoermer K.A.
        • Morrison T.E.
        Complement and viral pathogenesis.
        Virology. 2011; 411: 362-373
        • Ricklin D.
        • Lambris J.D.
        Complement in immune and inflammatory disorders: pathophysiological mechanisms.
        J Immunol. 2013; 190: 3831-3838
        • Lublin D.M.
        • Atkinson J.P.
        Decay-accelerating factor: biochemistry, molecular biology, and function.
        Annu Rev Immunol. 1989; 7: 35-58
        • Pavlov V.
        • Raedler H.
        • Yuan S.
        • et al.
        Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection.
        J Immunol. 2008; 181: 4580-4589
        • Raedler H.
        • Vieyra M.B.
        • Leisman S.
        • 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: 1397-1406
        • Gueler F.
        • Rong S.
        • Gwinner W.
        • et al.
        Complement 5a receptor inhibition improves renal allograft survival.
        J Am Soc Nephrol. 2008; 19: 2302-2312
        • Horwitz J.
        • Mathern D.
        • Heeger P.
        C3a receptor regulates the CD8 T-cell alloresponse via intrinsic and extrinsic mechanisms.
        Am J Transplant. 2018; 18: 498
        • Fang Y.
        • Xu C.
        • Fu Y.X.
        • et al.
        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: 5273-5279
        • Dempsey P.W.
        • Allison M.E.
        • Akkaraju S.
        • et al.
        C3d of complement as a molecular adjuvant: bridging innate and acquired immunity.
        Science. 1996; 271: 348-350
        • Marsh J.E.
        • Farmer C.K.
        • Jurcevic S.
        • et al.
        The allogeneic T and B cell response is strongly dependent on complement components C3 and C4.
        Transplantation. 2001; 72: 1310-1318
        • Wang H.
        • Arp J.
        • Liu W.
        • 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: 4451-4463
        • Valenzuela N.M.
        • McNamara J.T.
        • Reed E.F.
        Antibody-mediated graft injury: complement-dependent and complement-independent mechanisms.
        Curr Opin Organ Transplant. 2014; 19: 33-40
        • Stegall M.D.
        • Chedid M.F.
        • Cornell L.D.
        The role of complement in antibody-mediated rejection in kidney transplantation.
        Nat Rev Nephrol. 2012; 8: 670-678
        • Jane-Wit D.
        • Manes T.D.
        • Yi T.
        • et al.
        Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-kappaB signaling in endothelial cells.
        Circulation. 2013; 128: 2504-2516
        • Stegall M.D.
        • Diwan T.
        • Raghavaiah S.
        • et al.
        Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.
        Am J Transplant. 2011; 11: 2405-2413
        • Locke J.E.
        • Magro C.M.
        • Singer A.L.
        • et al.
        The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection.
        Am J Transplant. 2009; 9: 231-235
        • Burbach M.
        • Suberbielle C.
        • Brocheriou I.
        • et al.
        Report of the inefficacy of eculizumab in two cases of severe antibody-mediated rejection of renal grafts.
        Transplantation. 2014; 98: 1056-1059
        • Montgomery R.A.
        • Orandi B.J.
        • Racusen L.
        • 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: 3468-3478
        • Michielsen L.A.
        • van Zuilen A.D.
        • Muskens I.S.
        • et al.
        Complement polymorphisms in kidney transplantation: critical in graft rejection?.
        Am J Transplant. 2017; 17: 2000-2007
        • Wang Z.
        • Yang H.
        • Guo M.
        • et al.
        Impact of complement component 3/4/5 single nucleotide polymorphisms on renal transplant recipients with antibody-mediated rejection.
        Oncotarget. 2017; 8: 94539-94553
        • Griesemer A.D.
        • Okumi M.
        • Shimizu A.
        • et al.
        Upregulation of CD59: potential mechanism of accommodation in a large animal model.
        Transplantation. 2009; 87: 1308-1317
        • Michielsen L.A.
        • van Zuilen A.D.
        • Kardol-Hoefnagel T.
        • et al.
        Association between promoter polymorphisms in CD46 and CD59 in kidney donors and transplant outcome.
        Front Immunol. 2018; 9: 972
        • Budding K.
        • van de Graaf E.A.
        • Kardol-Hoefnagel T.
        • et al.
        A promoter polymorphism in the CD59 complement regulatory protein gene in donor lungs correlates with a higher risk for chronic rejection after lung transplantation.
        Am J Transplant. 2016; 16: 987-998
        • Loupy A.
        • Lefaucheur C.
        • Vernerey D.
        • et al.
        Complement-binding anti-HLA antibodies and kidney-allograft survival.
        N Engl J Med. 2013; 369: 1215-1226
        • Zeevi A.
        • Lunz J.
        • Feingold B.
        • et al.
        Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients.
        J Heart Lung Transplant. 2013; 32: 98-105
        • Witt C.A.
        • Gaut J.P.
        • Yusen R.D.
        • et al.
        Acute antibody-mediated rejection after lung transplantation.
        J Heart Lung Transplant. 2013; 32: 1034-1040
        • Wiebe C.
        • Gareau A.J.
        • Pochinco D.
        • et al.
        Evaluation of C1q status and titer of de novo donor-specific antibodies as predictors of allograft survival.
        Am J Transplant. 2017; 17: 703-711
        • Vakeva A.
        • Lehto T.
        • Takala A.
        • et al.
        Detection of a soluble form of the complement membrane attack complex inhibitor CD59 in plasma after acute myocardial infarction.
        Scand J Immunol. 2000; 52: 411-414
        • Budding K.
        • van de Graaf E.A.
        • Kardol-Hoefnagel T.
        • et al.
        Soluble CD59 is a novel biomarker for the prediction of obstructive chronic lung allograft dysfunction after lung transplantation.
        Sci Rep. 2016; 6: 26274
        • Tower C.M.
        • Reyes M.
        • Nelson K.
        • et al.
        Plasma C4d+ endothelial microvesicles increase in acute antibody-mediated rejection.
        Transplantation. 2017; 101: 2235-2243
        • Aibara N.
        • Ohyama K.
        • Hidaka M.
        • et al.
        Immune complexome analysis of antigens in circulating immune complexes from patients with acute cellular rejection after living donor liver transplantation.
        Transpl Immunol. 2018; 48: 60-64
        • Thurman J.M.
        • Le Quintrec M.
        Targeting the complement cascade: novel treatments coming down the pike.
        Kidney Int. 2016; 90: 746-752