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  • Review Article
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The role of complement in the early immune response to transplantation

Nature Reviews Immunology volume 12, pages 431–442 (2012)Cite this article

Subjects

Key Points

  • The complement system is primarily a host defence mechanism, but it causes injury to tissue cells through the formation of the membrane attack complex (C5b–C9), which leads to cell lysis and cell death, and through the stimulation of inflammation and antigen-specific immunity.

  • A central pool of circulating complement components (mainly produced by hepatic cells) is distinct from a peripheral pool of extracellular complement secreted by various tissue-resident cells and migratory leukocytes.

  • In most vital organs, ischaemia–reperfusion injury is mediated by complement components C5a and C5b–C9 and, as shown in a mouse kidney transplant model, this is strongly dependent on tissue-mediated production of C3.

  • The lectin pathway of complement activation is a common trigger of ischaemia–reperfusion injury in several organ models (initiated either by direct binding of the lectin to ischaemic tissue or via natural IgM), and the alternative pathway may significantly increase the deposition of complement at the site of activation.

  • Effective priming of CD4+ T cells that mediate graft rejection requires C3a and C5a, which are produced by dendritic cells and stimulate the presentation of alloantigens and the differentiation of naive CD4+ T helper (TH) cells to TH1 cells.

  • The reactivity of antigen-primed CD4+ and CD8+ T cells against donor cells is enhanced by the peripheral synthesis of complement and the generation of the effectors C3a, C3b and C5a.

  • Antibody-mediated rejection requires complement (specifically C3) not only for the efficient priming of B cells against alloantigens but also for the induction of inflammation and thrombosis (by C5a and C5b–C9) at the site of antibody binding in the graft.

  • Emerging therapeutic approaches include targeting the donor organ with complement regulators to prevent stress-induced injury and sensitization of the recipient, and treatment of the recipient to prevent complement-mediated vascular injury during antibody-mediated rejection and the recurrence of haemolytic–uraemic syndrome.

  • Imaging ligands that can be used to detect and quantify tissue-bound C3 at the site of tissue injury, as well as biomarkers that predict or associate with complement-mediated damage to the transplant, are allowing the significance of these findings to be addressed in humans.

Abstract

The complement system is a key element of the innate immune system, and the production of complement components can be divided into central (hepatic) and peripheral compartments. Essential complement components such as C3 are produced in both of these compartments, but until recently the functional relevance of the peripheral synthesis of complement was unclear. Here, we review recent findings showing that local peripheral synthesis of complement in a transplanted organ is required for the immediate response of the donor organ to tissue stress and for priming alloreactive T cells that can mediate transplant rejection. We also discuss recent insights into the role of complement in antibody-mediated rejection, and we examine how new treatment strategies that take into account the separation of central and peripheral production of complement are expected to make a difference to transplant outcome.

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Figure 1: The complement cascade and its control.
Figure 2: A model for the epithelial cell response to tissue stress.
Figure 3: Influence of complement on alloantigen presentation.
Figure 4: A proposed model by which the alloantibody response is modified by complement.
Figure 5: A toolkit for exploring the therapeutic and diagnostic potential of C3.

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Acknowledgements

This work was supported by the Medical Research Council (grant numbers G0600698 and G1001197). The research was also funded and supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas's NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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  1. Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, and NIHR Comprehensive Biomedical Research Centre, King's College London School of Medicine at Guy's, King's and St Thomas' Hospitals, London, SE1 9RT, UK

    Steven H. Sacks & Wuding Zhou

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Correspondence to Steven H. Sacks.

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Competing interests

Steven H. Sacks received a contribution from Alexion Pharmaceuticals to organize a national meeting of Complement UK in 2010. King's College London owns the intellectual property for mirococept.

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Supplementary information S1 (table)

Potential sources of complement during transplantation (and in some other non-transplanted tissues) (PDF 140 kb)

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Glossary

Complement cascade

There are three independent pathways that can lead to the activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes, the alternative pathway is triggered by direct C3 activation, and the lectin pathway is initiated by mannose-binding lectin (MBL) binding to the surface of microorganisms and other activating surfaces.

Xenotransplantation

The transplantation of organs, tissues or cells from one species to another.

Allotransplantation

The transplantation of organs, tissues or cells from a donor to a genetically non-identical recipient of the same species.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

Mannose-binding lectin

(MBL). A protein of the C-type lectin family that binds to carbohydrate structures such as mannose on the surface of many pathogens and other activating surfaces and triggers complement activation. It is composed of a number of identical subunits and is found as a complex in association with several serine protease molecules.

Major histocompatibility antigens

Highly polymorphic cell-surface glycoproteins (termed MHC molecules) that characterize different members of the same species and underlie the rapid rejection of organ, cell or tissue transplants between those individuals.

Minor histocompatibility antigens

Polymorphic peptides that are expressed by the donor tissue and recognized by recipient T cells, even when a transplant donor and recipient have identical major histocompatibility antigens. The amino acid differences in minor antigens can cause the graft to be slowly rejected. An example is the male H-Y antigen, which is recognized by a female recipient of the same mouse stain.

Minor histocompatibility antigen H-Y

H-Y is a protein encoded on the Y chromosome. T cells from females respond to peptides derived from this protein, and so H-Y is a male-specific minor histocompatibility antigen. Furthermore, T cell receptors (TCRs) specific for this antigen have been cloned and used to generate distinct lines of TCR-transgenic mice.

Small interfering RNAs

(siRNAs). Short (∼21-base-pair) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.

Paroxysmal nocturnal haemoglobinuria

An acquired defect of the membrane-expressed regulators of complement activation CD55 and CD59 that leads to intermittent complement-induced intravascular haemolysis, haemoglobin in the urine and thrombosis.

Haemolytic–uraemic syndrome

A combination of haemolytic anaemia, acute renal failure and thrombocytopenia that typically follows a gastrointestinal infection with the Escherichia coli strain O157:H7. In atypical cases, this syndrome is caused by a defect in complement regulation by a complement-regulatory protein (namely, CD46, factor H or factor I).

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Sacks, S., Zhou, W. The role of complement in the early immune response to transplantation. Nat Rev Immunol 12, 431–442 (2012). https://doi.org/10.1038/nri3225

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