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Kidney Transplantation: Past, Present, and Future

 Can Animals Provide Spare Parts For Humans? (3/28)

 By MICHAEL MCCARTHY
 c.1997 The Lancet

f your kidneys or heart were to fail or if a disease destroyed your lungs or liver, it is now possible that your life could be saved with an organ transplant - if a suitable organ were found.

 Today, however, too few organs are available for those who need them. As a result, thousands of people on transplant waiting lists die each year.

 Efforts to increase organ donations can help, but they are unlikely to solve this growing worldwide problem, writes a team of transplant specialists in this week's issue of The Lancet.

 The most promising solution, write Professor Robert Lechler and his co-workers at the Royal Postgraduate Medical School in London, is xenotransplantation: the transplantation of animal organs and tissue into humans.

 Not only could xenotransplantation end the organ shortage, Lechler says, but it would also provide an ``inexhaustible supply'' of tissue which could be used to treat a number of common diseases. If, for example, insulin-producing cells from an animal could be successfully transplanted into a human it may be possible to cure many people with diabetes.

 But before such treatments can become available, a number of formidable scientific problems must be solved, Lechler says. The most formidable challenge is to find a way to keep the human immune system from attacking the transplanted animal cells, a phenomenon called rejection.

 Our immune system is programmed to attack and destroy anything in our bodies it perceives to be foreign, and, in general, the more distantly related something is, the more vigorous the attack. Rejection always occurs to some degree when a transplant is performed - except when the organ donor and organ recipient are identical twins. In that case, because tissues donated by the twin are identical to those of the recipient, the recipient's immune system does not see them as foreign.

 But the less genetically similar the donor and recipient are, the more likely that the recipient's immune system will reject a transplanted organ. This is why transplant patients usually need to take drugs that suppress their immune system. MONKEYS VS. PIGS@<</a>

 ``On purely immunological considerations,'' Lechler says, ``primates would be the most suitable donors for human beings.'' That's because primates - chimps, monkeys and apes - are our closest animal relatives and, so, are the best genetic match we can find in the animal kingdom. Rejection does occur when primate organs have been transplanted into humans, Lechler says, but the rejection is similar to that seen in human-to-human transplants, and so may be medically manageable.

 But there are problems with using primates as a source of organs, Lechler says. First, primates are hard to raise in large numbers, for they reproduce slowly and take many years to mature, so it would be difficult to breed the numbers needed to meet the demand for organs.

 Second, because they are so closely related to humans, they may carry bacteria and viruses that can easily infect humans. HIV, the virus that cause AIDS, for example, is thought to be a monkey virus that jumped to humans.

 And finally many people feel it would be unethical to raise such highly intelligent and social animals only to kill them for their organs.

 ``Pigs, on the other hand, would make appropriate donors for many reasons,'' Lechler writes.

 ``They breed quickly, and we have extensive experience in raising them in large numbers. Fewer people are likely to have ethical qualms about using pigs as a source for organs. And, although pigs may carry dangerous infectious agents, it might be possible to raise `germ-free' stock.

 ``The principle drawback of porcine organs and the reason why they are not already used,'' Lechler writes, ``is that because pigs are so distantly related to humans, pig organs will trigger a severe, almost immediate immune attack when transplanted into humans, a reaction called a hyperacute rejection.''

 Within minutes of transplantation, antibodies and defensive proteins found in the blood attack the blood vessels within the transplanted pig organ, causing clotting which chokes off blood flow, quickly killing the organ.

 A number of strategies have been devised to try to prevent hyperacute rejection, Lechler says, some of which will be tested in humans in the next few years. One strategy is to find a way to soak up the antibodies that attack the pig cells. One way to do this would be to run the blood of a pig organ recipient through a filterlike device that contains molecules similar to those found on the surface of pig cells. As the patients blood passed through the filter, the anti-pig antibodies would bind to the filter and so be removed.

 Another way to approach this problem would be to inject the patient with molecules that will attach to and block the part of the antibodies that bind to the pig cells, thus preventing them from attacking the pig organ. These approaches, however, are only a temporary fix, Lechler says, because the immune system produces new antibodies relatively quickly.

 Another strategy would be to build a better pig. This could be done by creating a strain of pig that has been genetically altered so that its cells do not make the proteins to which human antibodies bind. It is also possible to insert human genes into pigs so that they produce human proteins which can neutralize the complement attack seen in hyperacute rejection.

 In experiments, hearts from such ``transgenic'' pigs have been able to survive up to 60 days in monkeys treated with immune-suppressing drugs, Lechler says.

 If these strategies can be made to work in humans, Lechler says, it may at least be possible to keep pig and other animal organs functioning in humans for several days or weeks. This may make it possible to use animal organs to sustain a person while he/she waits for a human organ.

 But Lechler points out such ``bridging xenografts'' would not solve the organ shortage and so would only serve to make the waiting list longer and longer. ``To be of significant benefit and to solve the (human) organ shortage, xenograft survival has to be eventually as good as that seen with human organ transplants,'' he says.

 What keeps this from being possible is a second kind of immune response that kicks in several days after xenotransplantation called ``delayed xenograft rejection.'' This form of rejection appears to be similar to that seen in human-to-human transplantation but is much stronger and more difficult to control with immune-suppressing drugs.

 Still, while not much is known about this physiology of delayed xenograft rejection, there may be ways to prevent it or at least make it less severe, Lechler says. It may be possible, for example, to develop finding treatments that suppress classes of immune cells that play an important role in xenograft rejection but allow other kinds of immune cells to function normally and be capable of fighting off infection.

 However, Lechler says, that once the problem of xenograft rejection is solved, it still remains to be seen how well pig and other animal organs can function within the human body, which is for them an alien environment.

 ``Some clues are available,'' Lechler writes, ``physiological and biochemical similarities between humans and pigs indicate that porcine organs, such as the heart and kidney, may function adequately in man, at least in the short term.''

 But it is not clear, he says, if a pig's liver can replace a human liver because the proteins that a transplanted pig liver will make - which will be pig, not human proteins - may not function as well as the proteins made by the human liver.

 ``It remains to be seen,'' Lechler says, ``whether this is one area where the use of primates will eventually become commonplace, since the available evidence suggests that baboon livers can function adequately in human beings.''

 Copyright 1997 by The Lancet

 NYT-04-01-97 0956EST

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