2001: Innovations in Transplantation

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2001: Innovations in Transplantation

ce A. Turka, MD

Medscape Transplantation 3(1), 2002. © 2002 Medscape Portals, Inc

Introduction

In most medical fields, the progress in basic, translational, and clinical

science is largely made in small increments. Such is also the case in

transplantation surgery and medicine. Nonetheless, it is often possible to

identify a few landmarks that redefined the field because they directly

translated into major improvements in patient and/or graft survival, enabled

new types of therapies to be delivered, or altered the ways in which

scientists and clinicians think about the field.

During the year 2001, 6342 articles were published regarding solid organ or

non-bone marrow tissue transplantation, as determined by searching the

MEDLINE database. It is obviously impossible to review them all. In the

context of this review, I have been given editorial license to approach the

topic as I choose. Rather than try to summarize multiple developments within

the field during the last year, I have chosen to highlight 2 areas, which,

in a few years' time, may be recognized as having been landmark

achievements. I have deliberately chosen 1 that represents basic or

preclinical work and 1 that represents clinical studies. I emphasize that

this is a highly personal view. It is meant to represent my own thinking

only, not a consensus of experts. I apologize in advance to the many

outstanding investigators whose work I omitted for reasons of space.

I believe that there are 2 separate areas of achievement which may, in

future years, be looked upon as watershed events for the field of

transplantation: the isolation and use of pig embryonic stem cells for the

development of gene-knockout pigs, and the successful and explosive

expansion of clinical islet transplantation programs.

Gene Targeting In Pigs

One of the major limitations in transplantation is the very limited supply

of organs and tissues. In the year 2000, according to the United Network for

Organ Sharing database, 22,953 transplants were performed in the United

States.[1] However, as of January 4, 2002, there were 79,446 patients

waiting for kidney, liver, heart, pancreas, or lung transplants. This number

has grown several-fold over the last 20 years and continues to increase. The

tremendous disparity between supply and demand is due in part to the success

of the field. Precisely because organ and tissue transplantation can work so

well are they seen as accepted therapies, even as treatments of choice, and

not just last-ditch efforts.

It is clear that even if all potential donors in the United States consented

to donation, we would still fall very far short of satisfying the demand for

organs. This has led to the concept of xenotransplantation, using pigs as

the preferred donor species for a variety of reasons including physiologic

compatibility, ease of breeding in captivity, large litter size, and ethical

acceptability. Early on, it was recognized that pig organs and tissues

underwent hyperacute rejection in humans, due to preformed antibodies

against a carbohydrate epitope created on pig cells by the enzyme

galactose-transferase (Gal-transferase), an enzyme in which humans and Old

World monkeys are deficient. Apparently, this sugar structure is found on

gut bacteria, and in humans is seen as a foreign antigen, eliciting

large-scale antibody production. Following grafting of pig tissues into

humans or Old World monkeys, the antibodies immediately bind the pig cells,

activate complement, and lead to hyperacute rejection.

The creation of transgenic pigs with human complement inactivators on pig

cells has successfully prevented hyperacute rejection. However, this has not

enabled long-term graft survival, as the anti-Gal antibodies that are still

present eventually stimulate cellular immune and inflammatory responses,

which have proven refractory to all therapies.

Very recently, 2 groups, working independently, have reported the isolation

of pig embryonic stem (ES) cells.[2,3] Moreover, each group has targeted and

deleted a single Gal-transferase allele in pig ES cells, and then used the

cells to create viable pigs. While these pigs still express Gal-transferase

on their cells (as only 1 of their 2 alleles has been deleted), they can be

interbred to generate homozygous Gal-transferase-deficient pigs. The next

step is to make sure these pigs are viable and their organs and tissues are

normal. If so, the key experiment will be to transplant those organs and

tissues into Old World monkeys to see whether hyperacute rejection is

overcome. Should this be the case, one would hope that pig

xenotransplantation would be as amenable to immunosuppression as

allotransplantation, potentially leading to a solution to the organ

shortage.

Although not discussed in detail, another area that is rapidly emerging is

the development of tissue-specific stem cells. In a variety of organs and

tissues, investigators are reporting the presence of primitive stem cells,

which may be capable of tissue regeneration. Moreover, it has been suggested

that hematopoietic stem cells may indeed be pluripotent. This clearly

presents the hope of an alternative solution (other than

xenotransplantation) to the organ and tissue shortage for human

transplantation. Hopefully, work in this area will progress to the point

where it is discussed in this space next year.

References

2000 Annual Report of the U.S. Scientific Registry of Transplant Recipients

and the Organ Procurement and Transplantation Network: Transplant Data

1989-1998. (February 21, 2000). Rockville, Md., and Richmond, Va:

HHS/HRSA/OSP/DOT and UNOS. Available at:

http://www.unos.org/Data/anrpt_main.htm. Accessed January 25, 2002.

Lai L, Kolber-Simonds D, Park K-W, et al. Production of

alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning.

Published online January 3, 2002; 10.1126/science.1068228 (Science Express

Reports). Available at:

http://www.sciencemag.org/cgi/search?volume= & firstpage= & author1=Lai+L & author

2= & titleabstract= & fulltext= & fmonth=Oct & fyear=2000 & tmonth=Jan & tyear=2002 & hits

=10 & sendit.x=23 & sendit.y=11. Accessed January 25, 2002.

World's first announcement of cloned 'knock-out' pigs. Public announcement

by PPL Therapeutics. Available at:

http://www.ppl-therapeutics.com/html/cfml/index_fullstory.cfm?StoryID=50).

Accessed January 25, 2002.

Shapiro AM, Lakey JR, EA, et al. Islet transplantation in seven

patients with type 1 diabetes mellitus using a glucocorticoid-free

immunosuppressive regimen. N Engl J Med. 2000;343:230-238.

Funding Information

ce A. Turka, MD, has no significant financial interests to disclose.

ce A. Turka, MD, is C. Mahlon Klein Professor of Medicine and Chief,

Renal Division at the University of Pennsylvania Health System,

Philadelphia; President of the American Society of Transplantation.

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