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Chapter 6 : Therapeutic Strategies for Xenotransplantation

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Abstract:

To achieve successful xenotransplantation, it is necessary to overcome the immunological barriers that evolution has built up between different species. In contrast to allotransplantation, where the cellular response is the main hurdle, in xenotransplantation both humoral and cellular responses have to be overcome. In attempts to achieve successful pig-to-human xenotransplantation, several approaches are currently being evaluated. Genetic engineering techniques are being applied to the problems of xenotransplantation. To achieve successful xenotransplantation, it will probably be necessary to combine several therapeutic techniques and/or agents, as is the case with allotransplantation today. Xenotransplantation offers the first opportunity for modifying the donor as opposed to the recipient, which opens up new possibilities in this era of rapidly developing techniques such as genetic engineering, gene transfer, and cloning. The breeding of a pig with a vascular endothelial structure against which humans have no preformed antibodies would be a major advance. In the recipient, however, it will still be necessary to inhibit the production of induced antibodies, as well as the strong cellular response, either by some form of immunosuppressive therapy or by the induction of tolerance.

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6

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White Blood Cells
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Major Histocompatibility Complex
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B Cells
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Bone Marrow
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Plasma Cell
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Figures

Image of Figure 1
Figure 1

Biosynthetic pathway for synthesis of Galαl-3Gal. The αl,3 galactosyltrans-ferase enzyme adds galactose to -acetyllactosamine (Gal1-4GlcNAc) to generate Galα1-3Gal. The same substrate can be utilized by transgenically introduced α1,2 fucosyltrans-ferase to produce the H histo-blood group epitope. Galαl-3Gal can also be eliminated by the introduction of α-galactosidase, which enables the N-acetyllactosamine substrate to be available again for further fucosylation. Modified from Sandrin et al. ( ).

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6
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Image of Figure 6
Figure 6

Anti-αGal IgG and IgM levels during treatment with anti-CD20 MAb (short arrows) and adsorption with EIA (long arrows). After four injections of anti-CD20 MAb and four of EIA, the level of anti-αGal IgM returned to pretreatment values within 2 weeks, whereas IgG remained below baseline.

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6
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Image of Figure 3
Figure 3

Anti-αGal IgG and IgM responses following porcine peripheral blood mobilized progenitor cell (PBPC) transplantation in representative baboons receiving a tolerance-inducing regimen without (a) and with (b) anti-CD40L MAb. The arrows indicate the first day of porcine PBPC transplantation, which was administered after the extracorporeal immunoadsorption of anti-αGal antibodies, (a) A rise in both anti-αGal IgG and IgM occurred by day 10, indicating sensitization to the Gal determinants on the PBPC. (b) No rise in αGal-reactive IgG or IgM occurred, indicating that sensitization to Gal did not develop when anti-CD40L MAb was administered. The non-αGal-reactive anti-pig antibody response is shown expressed as median fluorescence intensity (MFI), in the same representative baboons treated without (c) and with (d) anti-CD40L MAb. The first column represents the total anti-pig antibody level, column 2 represents the same serum after immunoadsorption of anti-αGal antibody over an αGal matrix, and column 3 represents this serum after further depletion over a pig cell matrix. The difference between columns 1 and 2 therefore indicates the amount of anti-αGal antibody, and the difference between columns 2 and 3 indicates the amount of non-αGal anti-pig antibody, (c) Antibody directed to porcine non-αGal determinants on the PBPC developed within 20 days, (d) No antibody against porcine non-αGal determinants developed.

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6
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Figure 4

Detection by flow cytometry of pig cell chimerism in the blood of a baboon pretreated with a nonmyeloablative regimen and anti-CD40L MAb. The pig cells were injected on days 0 to 2, with detection of pig cells constituting up to 16% of the white blood cells in the baboon. These cells stained positive for a pig marker (pan pig) and for pig CD9 and pig MAC (monocyte and granulocyte markers). After day 5, no pig cells were detectable until day 16, when a pig monocyte population could be detected until day 22, indicating pig cell engraftment in the baboon.

Citation: Bühler L, Basker M, Alwayn I, Sachs D, Cooper D. 2001. Therapeutic Strategies for Xenotransplantation, p 117-135. In Platt J (ed), Xenotransplantation. ASM Press, Washington, DC. doi: 10.1128/9781555818043.ch6
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