TRANSPLANTATION

What is transplantation?

Solid organ transplantation is the use of a donor organ to replace a diseased or damaged one. Transplantation can range from a relatively minor procedure, such as the graft of a cornea in the eye, up to complex operations to replace the heart and lungs or liver. Life-long suppression of the recipient's immune system is usually necessary to prevent rejection of the grafted tissue.

Bone marrow transplantation is a similar procedure in which the tissue transplanted is not solid, but is instead a suspension of bone marrow or blood stem cells that can repopulate the recipient's empty bone marrow spaces and recreate a functioning immune system. This may be done to permit the use of intensive chemotherapy to completely eliminate malignant cells, as in certain leukaemias. When the donor bone marrow comes from another individual - allogeneic bone marrow transplantation - life-long immunosuppression is required to prevent the newly transferred immune cells from destroying recipient organs, a reaction known as graft versus host disease (GVHD). Immunosuppression is not required if the bone marrow cells are taken from an individual and re-infused after chemotherapy - autologous bone marrow transplantation.

Who needs transplants?

Solid organ transplantation is a last-resort treatment aimed at preserving an acceptable quality of life when medical and other treatment has failed. When an organ such as the heart, liver or kidney, has suffered such damage that it can no longer function, or has to have its function replaced by a procedure such as dialysis in the case of the kidney, transplantation of a donor organ may be considered.

In addition to solid-organ transplants, there were 2,320 first blood and bone marrow transplants (841 allogeneic and 1,479 autologous) performed in the UK in 2004, the great majority for cancers such as leukaemia or lymphoma (see Leukaemia). More than 80 per cent of these transplants were of blood stem cells.

The first successful kidney transplant took place over 50 years ago. Today, the graft survival rate five years after transplant is typically over 75 per cent for a kidney taken from a dead person and over 85 per cent for one from a living matched donor. Heart transplants are also undertaken, although less frequently, because of the shortage of donor organs. The five-year patient survival rate is about 70 per cent. Other organs transplanted are the liver (first achieved in 1967, five-year graft survival rate about 65-70 per cent) and, less commonly, the pancreas (one-year survival rate about 80 per cent for kidney + pancreas transplants).

Current practice and shortcomings

The major success of transplant surgery over the past 30 years would not have been possible without a battery of medicines (Figure 2). Most of these are discussed in other sections (see Pain, Thrombosis, Fungal Infections, Bacterial Infections, Herpes), but immunosuppressive agents, essential to prevent graft rejection, are discussed here.

The earliest medicines used to suppress rejection, such as azathioprine and 6-mercaptopurine, are somewhat toxic when used alone and they now have only a supporting role to play. A major breakthrough was the discovery of a molecule called cyclosporin A (Sandimmun, Novartis) which is able to prevent the body's immune system from attacking the graft. Another key event was the introduction in around 1970 of tissue matching. Together, these two developments greatly enhanced success rates in transplantation. Cyclosporin has a fine line between working effectively and damaging the body. The original injected form (Sandimmun) also had an unpredictable absorption that made it necessary to monitor blood levels carefully, although the more recently introduced oral form (Neoral) gives more predictable blood levels. Cyclosporin is used together with prednisone and/or azathioprine to prevent acute rejection and for the prevention and treatment of GVHD. Specialist transplant centres often develop their own standard procedures for the use of such combinations, with larger centres that carry out more transplants often achieving better results than smaller centres.

Other immunosuppressants have been made available since the introduction of cyclosporin. Tacrolimus (Prograf, Astellas) is used in kidney, heart and liver transplants and the more recently launched sirolimus (Rapamune, Wyeth) is used in kidney transplantation. A fourth immunosuppressant, mycophenolate (Cellcept, Roche and the enteric-coated, delayed release form Myfortic, Novartis) is only for use in combination with cyclosporin and corticosteroids. Cyclosporin and tacrolimus block the activation of cells that attack the transplanted tissue and lead to graft rejection. Both are potentially damaging to the kidneys and may induce high blood pressure. Sirolimus does not show the same damage to the kidneys as cyclosporin and tacrolimus; however, it may also cause high blood pressure and raises blood triglyceride and cholesterol levels.

Two monoclonal antibodies have been made available for use together with immunosuppressive therapy in kidney transplantation. These are basiliximab (Simulect, Novartis) and daclizumab (Zenapax, Roche). They target a receptor for interleukin-2 which plays a key role in the rejection process. Both reduce rejection, reducing the need for steroids and the risk of infection.

What's in the development pipeline?

Everolimus (Certican, Novartis) is an immunosuppressant belonging to the same family as sirolimus. In Phase 3 trials, used with reduced-dose oral cyclosporin, steroids and basiliximab, everolimus has been found to be associated with acute graft rejection rates as low as 3.5 per cent at 6 months and reduced signs of kidney damage, as well as a low rate of infection with cytomegalovirus - a common problem in transplantation. Also at an advanced stage is a modified release form of tacrolimus.

Bristol-Myers Squibb is studying belatacept in Phase 3 trial for the prevention of kidney graft rejection. Also at Phase 3, Wyeth is continuing to develop sirolimus in kidney transplantation and for liver transplantation.

Pfizer has a completely new type of immunosuppressant in Phase 2 trial for kidney transplantation. Its CP-690,550 is an inhibitor of an enzyme that plays a key role in the development and function of T cells. Inhibiting this enzyme selectively should result in effective immunosuppression with fewer side-effects than seen with less targeted agents. Novartis is also investigating a compound (AEB071) that targets T cells and this is also in Phase 2 trial. Roche and BioCryst are collaborating to develop BCX-4208, another T cell targeted agent which is in Phase 1 trials.

Also at Phase 2 are ISA247 (Isotechnika), an immunosuppressant of the same type as cyclosporin which is also being investigated as a possible treatment for psoriasis, and the antiviral compound maribavir (Viropharma), to inhibit cytomegalovirus. This latter compound has shown encouraging preliminary results in a trial in stem cell transplantation.

The development of new and more selective immunosuppressants offers hope of a better future for those undergoing transplantation. However, its must not be forgotten that the main limitation today is the lack of availability of donor organs, which results in many patients dying before they can be given a transplant and efforts to address this problem are urgently needed.

FOR FURTHER INFORMATION CONTACT:

Transplant Support Network
The Temple Row Centre, 23 Temple Row, Keighley, BD21 2AH. Phone: 0800 027 4490 (Helpline)
Website: www.transplantsupportnetwork.org.uk

British Organ Donor Society (Body)
Balsham, Cambridge, CB1 6DL.
Phone: 01223 893636
Website: www.bodyuk.org