Chapter 3 : The Complement System as a Hurdle to Xenotransplantation

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This chapter discusses the role of complement in the pathogenesis of tissue injury in xenograft rejection and reviews methods to inhibit complement activation as part of strategies to achieve xenograft survival. It begins with a brief overview of the complement system. The complement system is composed of 35 plasma and membrane-associated proteins, which include control proteins and receptors on cell membranes that recognize various fragments that result from complement activation. The membrane-associated complement regulators are of great interest to xenotransplantation. Although soluble complement inhibitors that can be used in vivo are beginning to be developed, small nontoxic molecules that inhibit complement efficiently are not yet available. Some of the large molecules that have been successful to abrogate hyperacute rejection (HAR) of the xenograft in experimental animals may be useful, at least temporarily, to reduce reperfusion injury and prevent HAR. A recent report indicates that a hexadecemeric multiple peptide of the C1q-binding site from human IgGi inhibits lysis of pig red cells by human serum, with an I value of 1 μM. This study suggests that peptides derived from the C1q binding region of immunoglobulins could hold promise to inhibit activation of the classical complement pathway.

Citation: Dalmasso A. 2001. The Complement System as a Hurdle to Xenotransplantation, p 55-83. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch3
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Figure 1

Schematic representation of the main pathways of complement activation. Mechanisms for activator recognition and initiation of activation are unique to each pathway. Classical pathway C3- and C5-convertases are also utilized by the lectin pathway. Sites of action of complement inhibitors are indicated by interrupted lines.

Citation: Dalmasso A. 2001. The Complement System as a Hurdle to Xenotransplantation, p 55-83. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch3
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Generic image for table
Table 1

Proteins of the complement system

Citation: Dalmasso A. 2001. The Complement System as a Hurdle to Xenotransplantation, p 55-83. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch3
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Table 2

Effects of complement activation products on endothelial cells and vessels of the xenograft and blood cells of the recipient

Citation: Dalmasso A. 2001. The Complement System as a Hurdle to Xenotransplantation, p 55-83. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch3
Generic image for table
Table 3

Soluble inhibitors of complement activation used in models of xenotransplantation

Citation: Dalmasso A. 2001. The Complement System as a Hurdle to Xenotransplantation, p 55-83. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch3

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