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Targeting Complement at the Time of Transplantation

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Complement Therapeutics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 735))

Abstract

Complement activation occurs in at least two phases when an organ is transplanted into a naive recipient: during reperfusion with recipient blood particularly when the donor organ has undergone a significant period of ischaemia and then during acute rejection once the recipient immune system has recognised the donor tissue as non-self. Both of these reactions are most obvious in the extravascular compartment of the transplanted organ and involve local synthesis of some of the key complement components as well as loss of controls that limit the activation of the pivotal component C3. In contrast, sensitised individuals with pre-existing circulating antibodies have an immediate reaction against the transplant organ that is also complement dependent but is enacted in the intravascular space. All three types of injury (ischaemia-reperfusion, acute rejection, hyperacute rejection) have a critical effect on transplant outcome. Here we discuss therapeutic strategies that are designed to overcome the impact of these factors at the start of transplantation with the aim of improving long-term transplant outcomes. These include the concept of treating the donor organ with modified therapeutic regulators that are engineered to be retained by the donor organ after transplantation and prevent inflammatory injury during the critical early period. By targeting the donor organ with anchored therapeutic proteins, the systemic functions of complement including host defence remain intact. The control of complement activation during the first stages of transplantation, including the possibility that this will reduce the capacity of the graft for stimulating the adaptive immune system, offers an important prospect for increasing the longevity of the transplant and offsetting demand on the limited supply of donor organs. It also provides a model in which the benefits and indications for localised therapy to maximise therapeutic efficiency and minimise the systemic disturbance may be instructive in other complement-related disorders.

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Authors and Affiliations

  1. Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, 5th Floor, Tower Wing, Great Maze Pond, Guy’s Hospital, London, SE1 9RT, UK

    Steven Sacks, Julia Karegli, Conrad A. Farrar, Elham Asgari, Wuding Zhou & Richard A. Smith

  2. NIHR Comprehensive Biomedical Research Centre, Guy’s & St Thomas’ NHS Foundation Trust and King’s College London, 16th Floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK

    Steven Sacks, Julia Karegli, Conrad A. Farrar, Elham Asgari, Wuding Zhou & Richard A. Smith

  3. Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK

    Wilhelm Schwaeble

Authors
  1. Steven Sacks
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  2. Julia Karegli
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  3. Conrad A. Farrar
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  4. Elham Asgari
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  5. Wilhelm Schwaeble
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  6. Wuding Zhou
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  7. Richard A. Smith
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Correspondence to Steven Sacks .

Editor information

Editors and Affiliations

  1. Medicine, University Of Pennsylvania Department Of Pathology Laboratory Of, Philadelphia, Pennsylvania, USA

    John D. Lambris

  2. University of Colorado School of Medicin, Aurora, Colorado, USA

    V. Michael Holers

  3. Department of Pathology & Laboratory Med, University of Pennsylvania School of Med, Philadelphia, Pennsylvania, USA

    Daniel Ricklin

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Sacks, S. et al. (2013). Targeting Complement at the Time of Transplantation. In: Lambris, J., Holers, V., Ricklin, D. (eds) Complement Therapeutics. Advances in Experimental Medicine and Biology, vol 735. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4118-2_17

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