Xenotransplantation - Nonhuman Primates in Biomedical Research - page 389

are usually administered for 48 or 72 hours after any
invasive procedure, such as introduction of the intravas-
cular catheters or the actual organ transplant. In contrast,
antiviral agents, such as ganciclovir, are maintained for at
least 1 month and frequently throughout the course of the
experiment as activation of recipient cytomegalovirus
(CMV) has been associated with an increased incidence of
graft failure ( Mueller et al., 2004 ).

TABLE 16.2

Representative Immunosuppressive and
Supportive Drug Regimen used in Pig-to-Nonhuman
Primate Heart or Kidney Transplantation Experiments at
the University of Pittsburgh

Agent/Dose

1. Antithymocyte globulin (ATG) 1e10 mg/kg x2 i.v. (days e3
and e1) to reduce the CD3 þ T cell count to 500/mm 2 .

2. Human antihuman CD154mAb 25 mg/kg i.v. (on days e1,
0, 4, 7, 10, 14, 19, and weekly) to maintain a trough level of
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RESULTS AND COMPLICATIONS
Results
XenoTx has made significant progress during the past
25 years ( Cooper et al., 2007; Zhu et al., 2007; Pierson
et al., 2009 ), though not to the extent that clinical trials of
organ xenoTx are likely to take place within the next year
or two, though tissue xenoTx is already underway and
corneal and islet xenoTx trials are likely to occur in the
foreseeable future. With regard to organ xenoTx, hetero-
topic heart transplants have functioned for up to 6 months
( Kuwaki et al., 2005; McGregor et al., 2005 ) and orthotopic
heart transplants for nearly 2 months ( Vial et al., 2000;
McGregor et al., 2009 ). Kidney transplants have been
slightly less successful, largely to an increased incidence of
consumptive coagulopathy as a result of coagulation
dysfunction; graft survival has extended close to 3 months
( Cozzi et al., 2003; Yamada et al., 2005; Griesemer et al.,
2009 ). Orthotopic liver xenoTx has been associated with an
immediate fall in platelet count to dangerously low levels,
resulting in internal hemorrhagic complications within the
first week despite adequate hepatic function ( Ekser et al.,
2010 ). Pig lungs appear to be particularly susceptible to
injury, and graft survival generally remains less than
24 hours ( Cantu et al., 2007; Nguyen et al., 2007 ).
More successful results have been obtained in the field
of islet xenoTx, with diabetic monkeys being maintained in
a normoglycemic state for

g/ml.
3. Mycophenolate mofetil (MMF) by continuous i.v. infusion to
maintain a trough level of 3e6

400 m

g/ml.
4. Methylprednisolone 5 mg/kg/day i.m. on the days of ATG
administration and on day 0 (day of Tx) and day 1, tapering
to 0.5 mg/kg/day i.m. by day 6, and to 0.1 mg/kg/day i.m. by
day 10 (maintained throughout period of follow-up)
5. Prostacyclin 20 ng/kg/min by continuous i.v. infusion for
48 hours.
6. Dopamine 2e7

m

m g/kg/min by continuous i.v. infusion for

48 hours.
7. Ganciclovir 5 mg/kg/day as prophylaxis against cytomega-
lovirus infection for at least the first month.
8. Cimetidine 10 mg/kg x2 daily while intravascular catheters
are in situ to prevent peptic ulceration.
9. Heparin to maintain the aPTTat 150 s throughout the period
of follow-up.
10. Buprenorphine 0.01 mg/kg will be given 6e12 hourly i.v. for
at least the first 72 hours after any surgical procedure.
11. Cefazolin 10 mg/kg/x2 days i.v. for 48 hours after any
surgical procedure.

agents are also administered ( Kuwaki et al., 2005;
Ezzelarab et al., 2009 ), frequently making the post-Tx
protocol a complicated one (an example is illustrated in
Table 16.3 ). A prolonged state of immune suppression can
obviously be associated with complications, particularly
infection.
Efforts are being made by at least one group to induce
a state of 'immunological tolerance' in which, after initial
intensive immunosuppressive therapy, possibly including
whole body and/or thymic irradiation, all therapy can be
slowly withdrawn ( Yamada et al., 2005; Griesemer et al.,
2009 ). Based on results in allogeneic models, the theory is
that, when the immune system recovers, it will no longer
respond to donor-specific antigens, but will respond nor-
mally to other antigens, e.g., those expressed on bacteria
and viruses. This is clearly the ultimate goal of both alloTx
and xenoTx, but in xenoTx it would appear that there are
several hurdles, such as coagulation dysregulation, that
need to be surmounted before this approach is likely to be
successful. Furthermore, the intensive induction therapy
required can increase the risk of infectious complications.
Antibacterial and antiviral prophylactic agents are
therefore administered routinely ( Table 16.2 ). Antibiotics

6 months ( Cardona et al.,
2006; Hering et al., 2006 ), with one for

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12 months ( van
der Windt et al., 2009 ). Very few pig corneal transplants
have been carried out in nonhuman primates, but the results
have been encouraging with grafts from unmodified pigs
remaining viable for several months with local corticoste-
roids ( Pan et al., 2007 ). Red blood cells from genetically
modified pigs have been demonstrated to be preferable to
ABO-incompatible allo-transfusions, but not yet compa-
rable to ABO-compatible transfusions ( Long et al., 2009 ).

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Complications
Complications include those associated with intravascular
catheters, as mentioned above. Wound healing has not been
a significant problem, even when the recipients have