XENOTRANSPLANTATION


A new scientific breakthrough can save the lives of the 48,000 people who are in desperate need of an organ transplant. This new technique, not yet perfected by scientists, is called xenotransplantation. This is the process of transplanting animal cells and/or organs into humans in need. As you can see from this chart about a half of the people waiting received the human organ needed and the other half will unfortunately die because the demand is far grater than the supply.. Scientists hope with this new process those fatalities can be eliminated.

Animal parts such as pig heart valves and insulin made by cattle are already being used in humans . So it would only seem logical that the next step would be to use entire organs! This has been attempted several times in history but all attempts have failed.
The area of interest now turns to why these transplants are unsuccessful... why are the organs rejected? The main reason is one of common sense, a foreign substance is being introduced into the body. The human bodies immune system produces antibodies which attack the foreign organ. These antibodies are produced by a type of white blood cell called B-cells. When these molecules attach to the donated tissue they trigger complement proteins (which are produced by the liver and other tissues) that work with antibodies to destroy the foreign "invaders." (In this case the graft). The antibodies basically destroy the capillaries in the transplanted organ which in turn causes a massive hemorrhage. The endothelial cells which line the vessels normally keep the blood in a liquid state by producing proteins and surface enzymes which inhibit the collection of platelets. But when these cells fail to do their "job", and the recipients blood (in this case the human) meets the donor organ (which belongs to the pig) the humans platelets rush into the vessels and cut off the flow of blood. Research has shown that the xenoreactive natural antibodies (XNA's) and compliment proteins cause the endothelial cells to shrivel up, which accelerate the clotting process. This can be seen within minutes, as the organ begins to swell and blacken. The form of rejection common to this cross-species transplantation is called hemoral rejection or hyperacute rejection

Another area being tested is that of introducing leukocytes (a type of white blood cell) from the donor into the human in the attempt to stop rejection. This experiment was preformed on baboons.


The baboons had previously undergone radiation which depleted their bodies of bone marrow cells. This was done to ensure that once the pig marrow cells were injected into the baboon they would not be rejected. Another step to ensure success ( which I will further explain in a moment) was to filter the baboons blood of antibodies which would destroy the injected pig cells and also administered immunosuppressive drugs. The baboons immune system in time killed most of these transplanted cells, however some of the pig's DNA survived in one of the baboons used for close to a year.
Scientists have isolated the specific molecular fragments (the antigens) which are found on the animals tissue which the human antibodies attack. So the possibility of breeding animals (pigs in this case) which lack the targeted sugar group could solve the problem of rejection


In September of 1995 a British biotechnical company claimed that it had created livestock with human genes that have been incorporated into the animals protein, and whose organs could block the action of the proteins responsible for rejection. Transplantations done with these animals organs using monkeys as the recipients have been accepted longer in the body, rejected after two months rather than a couple of minuets or hours. Another possibility to prevent hemoral rejection is to suppress the recipients immune system in such a way so that it would be impossible to destroy the transplanted tissue. So by developing new drugs to modify (suppress) the body's natural response have reopened the possibility of cross-species transplantation. Some of these drugs are: FK506 which affects the T-lymphocytes by inhibiting the secretion of certain proteins that are needed for them to function.
Cyclophosphamide, also known as Cytoxan was initially developed to treat cancer, this results in stopping the production of antibodies which help destroy the foreign substance. Basically it inhibits the production of DNA which in turn prevents the growth of cells which would secrete the antibodies that cause the rejection. Prostaglandin E, which modifies the cytokines and other cells that create the inflammatory response seen in humoral rejections. If these drugs are taken together the immune system can be significantly suppressed which may lead to the acceptance of these organs.
Another concern of this transplantation is the introduction/ transmission of infection and disease. Because the immune system has been chemically suppressed the body cannot combat foreign diseases. Recent in-vitro experiments at the Institute of Cancer Research in London showed that a pig retro-virus can be infectiously transmitted to human cells. This is a main cause of death in transplantation recipients. The process by which diseases are introduced from the animal to the human recipients is called xenogeneic infection. Organisms that are harmless to the host can have devastating effects in humans. More than 150 infections are known that can be transmitted from animals to humans, theses are called zoonoses (examples are salmonella and rabies). The Centers for Disease Control and the U.S. Food and Drug Administration are developing guidelines for this type of transplantation. Inorder to avoid the risk of transmitting disesase to humans the animals selected for xenotransplantation would have to be brought up in isolation and their enviormnent strictley controlled by scientiests. Other concerns that were discussed in a recient conference at the National Academy of Sciences (NAS) were summarized in two reports one filed by the Institute of Medecine and another by the Nuffield Council on Bioethics in which both found that the benefits of xenotransplantation outway the "ethical" risks. A statement was released that said "xenotransplantation should continue provided there is rigorous regulations to ensure both the protection of the potential human recipients and adequate care of the involved animal. One way to achieve this goal is to gain informed patient consent for a procedure that has not yet been successful. The next topic was what animal would be more "ethically viable", and it was decided that pigs were the best animals to use rather than primates in this complicated process for many reasons:

1. Few serious diseases of pig origin have ever been seen in humans
2. Their organs size and physiology is similar to that of humans
3. Easy to raise, readily available
4. Breeds of pigs already exist that are "pathogen free"
5. Pigs have litters after a three-five month gestation period
6. Each birth yields approximately 6-16 piglets
7. Not a lot of ethical concerns with pigs arise that would if using primates

Some disadvantages in pigs however are:

1. Immunologically pigs are distantly related to humans
2. Therefore diseases can be transmitted
3. And physically pigs are less similar to humans

Why primates were ruled out as potential donors:

Although they are physically (meaning anatomically and physiologically) and immunologically similar to humans the more closely related species could more likely transfer infectious disease However the more distantly related species organs are more likely to be rejected. But primates are slow breeding, and due to the potential threat of extinction that could result from the extremely large practice of using primates for transplants out ways the potential benefits. So as you have heard many advantages and disadvantages to Xentotransplantation exist, I found in The Lancet a table that sums them up.... ADVANTAGES:

1. Inexhaustible supply...if large litters are used...organs would be available for people who are currently excluded from waiting lists
2.It would extend the therapeutic possibilities of transplantation , meaning help with other diseases...the example used is diabetes mellitus
3.Gives the opportunity for genetic manipulation of donor organs to influence recipient rejection responses
4. Would allowed planned, unhurried operations
5. Finally, Species differences in susceptibilities to disease ,may make xenografts useful for transplants in specific groups example those with HIV or Hepatitis B)


DISADVANTAGES:
1. Ethical concerns
2. Transmission of donor pathogens to human host
3. The emerging of recombinant viral strains of unknown pathogenicity
4. Transmission of human pathogens to xenograft
5. Physiological incombatabilities, including the potential for differential ageing of xenograft and recipient
6.Finally, Immunologically- potentially severe vascular and cellular rejection Even thought it may take many more years to perfect this new form of transplantations scientists will continue to experiment. Not to further their careers but to save a large portion of the human population.


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SOURCES
INTERNET (11/23/97)
(1) Berger, Alan H. "Xenotransplantation: The Ethics, the Science, the Risks",online, Animal Rights Resource Site, 7 pages

(2) FDA, "Fact Sheet on Xenotransplantation,"online, FDA Backgrounder, 5 pages

(3) Institute of Medicine, "Federal Guidelines Needed To Ensure Safety In Animal-To-Human Organ Transplants,"online, Institute of Medicine, 4 pages

(4) UPMC, "Xentotransplantation Program Background," online, UPMC Health System, 2 pages

(5) UMPC, "Control of Rejection In Xenotransplantation,"online, UPMC Health System, 3 pages

(6) UPMC, "Virological Concederations In Xenotransplantation,"online, UPMC Health System, 3 pages

(6) Roush, Wade. "New Ways to Avoid Organ Rejection Buoy Hopes." Science, October 13, 1995. v270, n5234. p234-235.

(1) Dorling, Anthony, Riesbeck,Kristian, et al. "Clinical Xenotransplantation of Solid Organs." The Lancet, March 22, 1997. v349, n9055. p867-872.

(3) Baker, Beth. "Experts Ponder the Ethics of Xenotransplantation." BioScience, October 1996. v46,n9. p643.

(4) Marwick, Charles. "British, American Reports on Xennotransplantation." The Journal of the American Medical Associaltion, August 28, 1996. v276 n8. p589- 590.