3. How Well Does Xenotransplantation Work?

Research on xenotransplantation is still developing. The focus is on finding out whether it can work and, if so, whether it is safe for use in humans. Because of rejection and other problems such as size and shape, animal organ transplants will be the hardest procedures to perfect and may never be successful. Instead, researchers predict that in the short-to-medium term animal cell therapies (such as brain or pancreatic islet cells) or animal external therapies (such as devices using animal liver cells, or skin grafts) are more likely to be successful. This is because cell transplants and external procedures cause less immune rejection than organ transplants and present fewer structural and functional problems. These kinds of procedures are already being tested in limited clinical trials overseas. It is therefore these procedures, rather than organ transplants, that are likely to be the subject of the initial research proposals considered in New Zealand.

The following summary briefly describes the current state of research on each of the three types of animal transplantation procedures described in What is Xenotransplantation?.

Animal external therapies

The use of external machines containing animal liver cells to treat acute liver failure has been tested in many animal-to-animal studies, with some promising results. The Food and Drug Administration in the United States and the relevant authorities in Europe have therefore allowed clinical trials of pig liver dialysis procedures. Although not conclusive, these animal-to-human trials have shown some success with 'buying time' for patients with liver failure who are waiting for a suitable liver transplant from a human donor. Importantly, the use of pig liver cells in this way has not caused any significant adverse effects. Some bigger trials are now planned overseas to obtain better information about the effectiveness of the procedure.

There have also been encouraging results from both animal studies and clinical trials of techniques to grow human skin on feeder layers of animal cells, then using the skin to repair burns.

Animal cell therapies

Animal cell therapies involve the transplantation of isolated animal cells or cell clusters. They have the potential to treat diseases, such as type 1 diabetes, Parkinson's disease and Huntington's disease. They may also be able to be used to repair damaged tissues or organs, thus avoiding the need for more invasive surgery.

Research on animal cell therapies is at an early stage, although some islet cell transplants for Type 1 diabetes was trialled in New Zealand in the mid-1990s. Some success has been achieved in animal-to-animal studies, with good survival of the transplanted cells and minimal side-effects. Based on these results, agencies in the United States and Europe have approved a number of animal-to-human trials of animal cell therapies. Some of these have already been carried out. For example, promising clinical outcomes have resulted from the implantation of neural cells from foetal pigs into the brains of patients with Parkinson's disease. Others are either planned or are in progress.

So far, these clinical trials have included very few patients and the results obtained do not clearly show that animal cell therapies are effective. However, in many cases the cells survived well in the recipient and did not cause unwanted side-effects. Further animal-to-animal research is now being carried out to discover how to promote the function of the cells as well as their survival.

Animal organ transplants

There are major obstacles to the transplantation of whole organs between species. This was shown by a succession of failed attempts from the 1960s to the early 1990s. For animal organ transplants to be successful, researchers need to prevent the transplant being rejected by the recipient's immune response (because it recognises the transplant as 'foreign' and attempts to destroy it) and also to ensure that the organ functions properly. Rejection occurs in three ways: hyperacute rejection, delayed organ rejection and cellular rejection. The physiological processes involved are extremely complicated, and they present huge challenges to the success of xenotransplantation.

In recent years researchers have been using gene technology to genetically modify pigs to overcome the most severe forms of immune rejection. As a result, the survival times of animal-to-animal organ transplants have increased from minutes or hours, to days or weeks. Researchers think that these times may continue to improve as the science is better understood, new modifications are made to the source animals, and improved immunosuppressant drugs are developed and tested. Another approach has been to encapsulate the xenograft in a membrane that allows some molecules to pass through but keeps out the large molecules (such as antibodies) that are responsible for the immune response. Once again, there are a variety of technical problems that must be overcome. However, South Korea announced at the beginning of 2004 a 10-year plan to mass produce genetically altered pig organs for human transplants.

In summary, although animal-to-animal studies are being carried out in various countries, there is clearly a long way to go before such transplants can be tested in humans.

Which animals work best?

It would seem obvious, when searching for ways to reduce the rejection reaction to xenografts, to use animals as physiologically close to humans as possible, such as old world monkeys and the apes (for example, chimpanzees). However, this very closeness creates complex ethical problems as well as an increased likelihood of cross-species infection. There are strict regulations in New Zealand about the use of non-human primates in research, so it is unlikely that these species would be used for xenotransplantation research in this country.

At present the pig is the favoured animal for research into xenotransplantation, because they grow quickly to about the right size, produce large litters and can be reared in specific pathogen-free conditions (where some but not all micro-organisms are excluded). In terms of ethical concerns, the fact that pigs have long been used as a source of meat reduces - but certainly does not eliminate - the concerns of many people, especially when weighed against the possible benefits. However, recently it has become clear that there is also the possibility of cross-species infection from pigs. This takes the issue of whether to perform such a procedure out of the realm of an individual decision to take a personal risk, usually for the sake of a therapeutic effect, into the realm of the safety of the xenotransplantation recipient's close contacts and the community at large. The spectre of HIV and AIDS hangs over discussions on the possibility of cross-species infection, so we will now turn to look at the risks involved with xenotransplantation.

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