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Chapter 1 : A Primer on Xenotransplantation

Author: Jeffrey L. Platt1
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Affiliations: 1: Departments of Surgery, Immunology, and Pediatrics, Mayo Clinic, Rochester, MN 55905
Content Type: Monograph
Publication Year: 2001

Category: Immunology

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Abstract:

No area of medicine stimulates as much excitement or as much controversy as transplantation. The rationale for xenotransplantation is the shortage of human organs and tissues. For several reasons, however, most in the field of xenotransplantation have abandoned the use of nonhuman primates. Therefore, instead of using primates, most in the field of transplantation focus on the use of pigs or other non-primate species. If opportunities offered by xenotransplantation are great, the hurdles, at present, appear equally so. These hurdles include (i) the immune response of the host against the graft leading to rejection of the graft, (ii) the inherent physiologic limitations of the animal tissue or organ in a human system or induced disruption of the normal functions of the recipient, and (iii) the possibility of transferring infectious agents from the transplant to the recipient and, potentially, more broadly to the general population. This chapter focuses on the hurdles to transplanting porcine organs and cells into humans. The past few years have brought significant progress in defining the hurdles to xenotransplantation and progress in overcoming the immunologic and physiologic hurdles in this field.

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
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A Primer on Xenotransplantation
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Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
/content/10.1128/9781555818043.chap1.fig1-1
Figure 1

The immunological responses to xenotransplantation of various tissue types. Xenografts of free tissues such as pancreatic islets or isolated cells such as bone marrow cells are subject to early failure due to primary non-function, failure to neovascularize, or molecular incompatibilities and subsequent cell-mediated rejection. A porcine organ transplanted into a human would be subject to one or more of the immunological reactions shown here. Transplantation into an untreated recipient would give rise to hyperacute rejection. If hyperacute rejection is avoided, for example, by the inhibition of complement, the graft is subjected to acute vascular rejection. If anti-donor antibodies are depleted from the recipient, the graft may undergo accommodation, a condition in which acute vascular rejection does not occur despite the presence of anti-donor antibodies in the circulation of the recipient. If acute vascular rejection is avoided, the graft will undergo cell-mediated rejection or chronic rejection.

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10.1128/9781555818043/fig1-1.gif
Image of Figure 1
Figure 1

The immunological responses to xenotransplantation of various tissue types. Xenografts of free tissues such as pancreatic islets or isolated cells such as bone marrow cells are subject to early failure due to primary non-function, failure to neovascularize, or molecular incompatibilities and subsequent cell-mediated rejection. A porcine organ transplanted into a human would be subject to one or more of the immunological reactions shown here. Transplantation into an untreated recipient would give rise to hyperacute rejection. If hyperacute rejection is avoided, for example, by the inhibition of complement, the graft is subjected to acute vascular rejection. If anti-donor antibodies are depleted from the recipient, the graft may undergo accommodation, a condition in which acute vascular rejection does not occur despite the presence of anti-donor antibodies in the circulation of the recipient. If acute vascular rejection is avoided, the graft will undergo cell-mediated rejection or chronic rejection.

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
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Figure 2

Possible ways in which Galαl-3Gal expression could be decreased by genetic engineering. Synthesis of Gal1-3Gal is catalyzed by 1,3-galactosyltransferase (GT); the biosynthetic pathway is shown by dashed arrows. This enzyme adds galactose residues at the termini of oligosaccharide chains. Four possible approaches to preventing the synthesis of the sugar are shown by normal arrows. First, the expression of antisense RNA or a ribozyme might disrupt the structure or function of the GT mRNA. Second, introduction of a gene for an inhibitory ligand for GT, such as an appropriate Fv (an antibody-like molecule) or an aptamer (a small oligonucleotide inhibitor), might inhibit the function of the enzyme. Third, overexpression of another glycosyl transferase, such as H transferase, which adds fucose residues, might compete for the subterminal residues on oligosaccharide chains. This has been achieved in rats by the overexpression of a human H transferase, resulting in the addition of fucose rather than Gal1-3Ga1 to oligosaccharide side chains ( ). Fourth, expression of a glycosidase, such as a-galactosidase, might lead to cleavage of the antigenic saccharide chains. Reprinted by permission from 392(Suppl.):l 1-17, 1998, Macmillan Magazines Ltd.

10.1128/9781555818043/fig1-2_thmb.gif
10.1128/9781555818043/fig1-2.gif
Image of Figure 2
Figure 2

Possible ways in which Galαl-3Gal expression could be decreased by genetic engineering. Synthesis of Gal1-3Gal is catalyzed by 1,3-galactosyltransferase (GT); the biosynthetic pathway is shown by dashed arrows. This enzyme adds galactose residues at the termini of oligosaccharide chains. Four possible approaches to preventing the synthesis of the sugar are shown by normal arrows. First, the expression of antisense RNA or a ribozyme might disrupt the structure or function of the GT mRNA. Second, introduction of a gene for an inhibitory ligand for GT, such as an appropriate Fv (an antibody-like molecule) or an aptamer (a small oligonucleotide inhibitor), might inhibit the function of the enzyme. Third, overexpression of another glycosyl transferase, such as H transferase, which adds fucose residues, might compete for the subterminal residues on oligosaccharide chains. This has been achieved in rats by the overexpression of a human H transferase, resulting in the addition of fucose rather than Gal1-3Ga1 to oligosaccharide side chains ( ). Fourth, expression of a glycosidase, such as a-galactosidase, might lead to cleavage of the antigenic saccharide chains. Reprinted by permission from 392(Suppl.):l 1-17, 1998, Macmillan Magazines Ltd.

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
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Tables

A Primer on Xenotransplantation
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Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
/content/10.1128/9781555818043.chap1.tab1-1
Table 1

Xenograft classification

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10.1128/9781555818043/tab1-1.gif
Generic image for table
Table 1

Xenograft classification

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
/content/10.1128/9781555818043.chap1.tab1-2
Table 2

Activation of complement via the alternative pathway on xenogeneic cells

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10.1128/9781555818043/tab1-2.gif
Generic image for table
Table 2

Activation of complement via the alternative pathway on xenogeneic cells

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1
/content/10.1128/9781555818043.chap1.tab1-3
Table 3

Factors implicated in the initiation of acute vascular rejection

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10.1128/9781555818043/tab1-3.gif
Generic image for table
Table 3

Factors implicated in the initiation of acute vascular rejection

Citation: Platt J. 2001. A Primer on Xenotransplantation, p 3-28. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch1

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