Xenotransplantation - Nonhuman Primates in Biomedical Research

Biomedical Engineering Reference

In-Depth Information

As New World monkeys and all other mammals express

the Gal antigen, the experimental animals used in xenoTx

have involved the pig as the organ source and Old World

nonhuman primates as recipients. As work in the field of

xenoTx has progressed, it has also become realized that

pigs could act as a source of other tissues, such as skin,

ligaments, neural cells (for the treatment of conditions

such as Parkinson's disease), corneas (for corneal xenoTx),

and red blood cells (for clinical transfusion). Xeno-

transplantation, therefore, has an immense potential in

medicine, and, if it could be carried out successfully, would

lead to a revolution in therapy for a multitude of pathologic

conditions.

TABLE 16.1

The Advantages and Disadvantages of the

Pig as a Potential Source of Organs andCells for Humans,

in Contrast with those of the Baboon in this Role

Pig

Baboon

Availability

Unlimited

Limited

Breeding potential

Good

Poor

Period to

reproductive maturity

4e8 months

3e5 years

Length of pregnancy

114

2 days

173e193 days

Number of offspring

5e12

1e2

Growth

Rapid (adult

human size within

6 months) a

Slow (9 years to

reach

maximum size)

HISTORY

Xenotransplantation has a long history, both in the exper-

imental laboratory and in clinical practice ( Taniguchi and

Cooper, 1997; Cooper and Lanza, 2000 ). As early as the

eighteenth century, blood transfusions were carried out

from animals to man. Corneal Tx was first performed in

1838, more than 60 years before the first corneal alloTx in

1905 (reviewed in Hara and Cooper, 2011). Early clinical

attempts at organ xenoTx date back to the early 1990s. Of

particular note are the chimpanzee kidney transplants per-

formed in a series of 13 human patients by Reemtsma et al.

(1964) , and the baboon kidney transplants performed by

Starzl et al. in the 1960s (reviewed in Taniguchi and

Cooper, 1997 ). The first clinical heart transplant ever per-

formed (by Hardy et al. in 1964 ) involved the Tx of

a chimpanzee heart. Other notable clinical attempts were

by Starzl in relation to liver xenoTx, beginning in the 1960s

and continued into the 1990s, using both chimpanzees and

baboons as sources of organs (reviewed in Hara et al.,

2008 ). Although Reemtsma reported that one of his patients

remained well for 9 months supported by a pair of

chimpanzee kidneys, the other trials generally failed within

weeks ( Reemtsma et al., 1964 ). Efforts involving pig

organ transplants were universally unsuccessful within

hours or days.

Experimental models have used varying donor and

recipient species, but, since 1986, the pig-to-nonhuman

primate model has become the standard for research in this

field ( Lexer et al., 1986; Cooper et al., 1988 ). The most

commonly used surrogates for humans have been the

baboon (Papio species) and the cynomolgus monkey

(Macaca fascicularis). Both of these species mimic humans

in producing significant levels of anti-Gal antibody as well

antibodies directed to other antigens, known as anti-nonGal

antibodies, the antigenic targets of which remain unknown.

Investigations have included both heterotopic and ortho-

topic heart or liver xenoTx, kidney xenoTx, ex vivo lung

perfusion and lung xenoTx, islet or corneal xenoTx, the

xenoTx of neural cells and the transfusion of pig red blood

Inadequate b

Size of adult organs

Adequate

Cost of maintenance

Significantly lower

High

Anatomical similarity

to humans

Moderately close

Physiological

similarity to humans

Moderately close

Relationship of

immune system to

humans

Distant

Knowledge of tissue

typing

Considerable

(in selected herds)

Limited

Necessity for blood

type compatibility

with humans

Probably

unimportant

Important

Experience with

genetic engineering

Considerable

None

Risk of transfer of

infection

(xenozoonosis)

Low

High

Availability of

specific pathogen-

free animals

Ye s

Public opinion