A World of Xenografts without Hyperacute Rejection
Since the 17th century, when a dog bone was allegedly used to repair the skull of a Russian aristocrat, xenotransplantation technology has come a long way. Today, we have had experiences in transplanting not only bones, but also such complex organs as kidneys and hearts. However, xenotransplantation still faces some major obstacles including a serious shortage of donor organs, and hyperacute rejection of some organs after transplantation. Fortunately, a number of new approaches to solving these problems are being successfully explored. Some of them were presented at the recent BIO 2000 conference held in Boston, USA.
One of the new approaches, directed at solving the problem of hyperacute rejection, involves the transplantation of thymokidneys. A thymokidney is a kidney with vascularized autologous thymic tissue under its capsule. A recent study lead by Dr. David Sachs of the Massachusetts General Hospital in Boston, USA, demonstrated that vascularized thymic grafts were tolerated in large animals. The next step for Dr. Sachs group will be to test induction of tolerance with thymokidney across the major histocompatibility complex (MHC) II mismatch barrier.
Another strategy is being developed by PPL, a biotechnology company based in Scotland. PPL is hoping to create transgenically cloned pigs with a specific gene inactivated to avoid rejection. Pig organs are considered to be the best option for transplantation with humans because of their similarity to human organs both in size and function. While there are some concerns regarding potential retrovirus transmission, little debate has occurred regarding the ethical appropriateness of using pig organs.
Creating transgenic pigs is extremely challenging and will rely on the completion of two steps: the successful cloning of pigs, and the successful knock-out or inactivation of a gene(s) that plays a crucial role in organ rejection. Both steps require a significant amount of research as well as a little bit of luck. Fortunately, the first step has been completed: five healthy piglets have just been cloned. The gene knock-out study on cloned pigs can now begin. One of the primary 'candidates' for the knock-out is a gene responsible for the natural killer T-cell reaction, which is often the primary reason for xenotransplant organ rejection. Thus, we may soon have a xenograft option, which is well tolerated and is also available in virtually unlimited numbers.
Another interesting approach, which is currently being tested by various labs, involves construction of bio-artificial organs. This approach depends on the availability of building materials, which are primarily embryonic human stem cells and natural or artificial polymers. Because of some similarity between this procedure and cloning, there is an on-going ethical debate about whether these stem cells are in fact embryos and, thus, whether this strategy is altogether appropriate.
In conclusion, major improvements in xenograft transplantation technology are currently being made. Trials with humans using whole animal organs have not yet been undertaken. However, trials with cells and tissue, such as Genzyme's Nucrocell PD and HD (for Parkinson's and Huntington's diseases), and extra-corporeal assist devices, such as Circe Biomedical's HepatAssist liver support system, are currently underway.
Suggested Reading
- Genetic Engineering News 2000, 20(8): 1,28,73.
- Carlson BM. Stem cells and cloning: what's the difference and why the fuss? Anatomical Records 1999, 257:1-2.