Biomedical Engineering Reference
In-Depth Information
the production of Gal oligosaccharides, has clearly been
important (
Phelps et al., 2003; Kolber-Simonds et al.,
2004
). The insertion of a human gene to provide
protection of a pig organ has also played a major role,
particularly in regard to the introduction of a human
complement-regulatory protein, e.g., CD46 (membrane
cofactor protein), CD55 (decay-accelerating factor), or
CD59, to protect against the effects of complement
activation (
Cozzi and White, 1995; Loveland et al.,
2004
). Today, major efforts are being directed towards
expressing human anticoagulant, antiplatelet, anti-
inflammatory genes, such as tissue factor pathway
inhibitor, thrombomodulin, endothelial cell protein C
receptor, CD39, or hemeoxygenase-1 (HO-1).
An effort is also being made to provide local, rather than
systemic, immune suppression to the graft by, for example,
expression of pig or human CLTA4-Ig on graft cells.
Expression of this agent results in costimulatory blockade,
thus preventing T cell activation, which has been clearly
demonstrated by in vitro assays. However, when pCTLA4-
Ig was expressed constitutively, the pigs were found to be
partially immuno-incompetent and susceptible to infectious
complications (
Phelps et al., 2009
). Techniques are now
available to overcome this problem in some cases by
expressing the gene only in the tissues to be transplanted,
e.g., in the pig islets alone using an insulin promoter.
'Anticoagulant' or 'anti-inflammatory' genes, e.g., tissue
factor pathway inhibitor, CD39, that might similarly be
problematic if expressed widely in the pig, have also been
introduced only into the islets.
Techniques of genetic engineering that allow a gene to
be 'switched on' or 'off', such as those using the Cre-Lox
system, are currently being explored, as this would allow
the gene to be expressed functionally only in the organ after
Tx, but not in the pig before organ 'donation'.
neurodegenerative conditions, such as Parkinson's disease,
underwent clinical trials more than a decade ago, and these
may be resumed if current experiments prove encouraging
(
Badin et al., 2010
). With both islet and neural cell trans-
plantation, the risks to the patient are small, but the benefits
could be considerable.
XenoTx of whole organs requires further significant
advances in the laboratory before it can be ethically intro-
duced into the clinic, but bridging of patients in fulminant
liver failure by a pig liver while they await a human organ
may well be feasible within a few years (
Ekser et al., 2009
),
as may bridging with a pig heart in patients who are
awaiting human heart transplantation (
Cooper et al., 2000
).
The potential of xenoTx is so great that experimental
research is likely to continue and expand. However, it is
personnel-intensive, time-consuming, and expensive. As
the only relevant model is the pig-to-nonhuman primate
model, progress will inevitably be relatively slow. Our
increasing ability to genetically engineer pigs for this
purpose, however, provides optimism that the remaining
problems will be overcome.
ACKNOWLEDGMENTS
We are most grateful to Burcin Ekser, MD, for kindly providing
Figure 16.3
. Work on xenotransplantation in the Thomas E. Starzl
Transplantation Institute of the University of Pittsburgh is supported
in part by NIH grants U01 AI068642 and R21 A1074844, and by
Sponsored Research Agreements between the University of Pittsburgh
and Revivicor, Inc., Blacksburg, VA, USA.
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SUMMARY
Wild-type pig tissues, such as small intestinal submucosa
(SIS, which is rendered void of cells and is repopulated
with recipient cells) are already being used extensively in
clinical surgical practice. GTKO pig tissues, to which there
is a reduced inflammatory response, will probably be the
next innovation in clinical practice. In view of the world-
wide shortage of human corneas for Tx, the pig cornea is
likely to find a significant role in the treatment of corneal
blindness, particularly in less-developed countries; the
genetically modified pigs can be bred and housed in
a country with the necessary resources, and the corneas
shipped to the centers where they will be transplanted.
Clinical trials of islet xenoTx will probably take place
within the next few years (
Hering, 2009
). The need is vast,
and the supply of human islets limited. The xenoTx of
dopamine-producing neural cells for
the treatment of
