PhD MS BS
Director of Research Administration
Thomas E Starzl Transplantation Institute
Organ transplantation has become an increasingly effective option for treating endstage diseases, with 24,764 transplants being performed in the USA in 2002. However, the number of patients awaiting transplantation has continued to exceed the number of available organs. During this time, 86,222 patients were on the waiting lists and 6,386 died while waiting.(1) Over the past 10 years, the development of potent immunosuppressive regimens has greatly reduced the incidence of acute cellular rejection, leading to remarkable improvement in short-term patient and graft survival. However, there has been relatively little impact on long-term (more than five years) survival.
An allograft is an organ or tissue that is transplanted from one member of a species to another member of the same species. Except in rare cases of genetic identity between the donor and the recipient, it leads to an immune response. If this alloimmune response is allowed to proceed without any intervention (ie, immunosuppression), the transplanted organ or tissue will be rejected after several days to a few weeks. During this rejection process, donor alloantigens are processed and presented by specialised antigen-presenting cells in the secondary lymphoid organs (ie, draining lymph nodes and spleen), where naive T-cells become activated by the recognition of donor alloantigens. These allospecific T-cells then begin to proliferate and differentiate into helper and cytotoxic T-cells. Once the T-cells have differentiated into effector cells, they recirculate to the graft organ or tissue, where they will either directly kill the allogeneic target cells or provide help for B-cell activation and the production of complement-fixing antibodies, both mechanisms eventually leading to the destruction of the graft.(2) This immunological reaction is the outcome that needs to be prevented after transplantation.
Great strides have been made over the last 50 years in understanding the dynamic cascade of immune events that occur when the body recognises nonself from self. Nonetheless, the immunobiology of allograft rejection still remains something of a mystery with respect to the underlying mechanisms involved. Only through continual exploration of these immune processes will the complexities of allograft rejection be unravelled, leading to the discovery of novel targets for developing safer and more effective strategies for the elimination of allograft rejection and for the preservation of allograft survival and function.
We are in a transitional period in transplantation where we can appreciate the serious side-effects of conventional immunosuppression but are not yet able to manipulate the immune system in such a way as to make immunosuppression unnecessary. There are a number of important drawbacks to the use of standard immunosuppression, particularly if we accept that tolerance induction (acceptance of the allograft without continuous immunosuppression) is an important goal in transplantation. There is increasing evidence that, in some patients following transplantation, recognition of donor antigen by the immune system results in the development of specific immunological tolerance and acceptance of the graft. If this occurs, immunosuppression may be dramatically reduced or even withdrawn completely without triggering graft rejection. This drug-free state is the ideal outcome following transplantation and our ultimate goal.
Although immunosuppression is used to prevent and treat rejection, we are currently unable to predict who will develop graft rejection or which rejection episodes will lead to graft loss. In addition, there are two important barriers to progress in the development of new post-transplant drug protocols. First, we do not know how to induce graft acceptance or even how it occurs, and second, we have no reliable way of detecting graft acceptance before withdrawal of immunosuppression. The development of assays to identify patients who demonstrate donor antigen-specific hyporeactivity is now feasible. It is hoped that these assays will serve as a guide for the reduction and possible removal of immunosuppressive agents from stable allograft recipients.(3)
If we are to promote graft acceptance, we may need a different approach to immunosuppression in which early allorecognition is encouraged but the harmful effector responses, which result in graft rejection, are inhibited. There are two ways in which this might be attained. First, the use of calcineurin inhibitors could be avoided in the first few days after transplantation, allowing initial allorecognition and potential tolerising interactions to take place, or second, newer immunosuppressive agents that do not block tolerance induction in experimental models could be used instead.(3) Until these two issues are addressed, any approach will inevitably involve a compromise between the risk of losing the graft to rejection or the toxicity of the drugs. A number of strategies may be used to safely reduce immunosuppression.
Tolerance-inducing immunosuppressive strategy
One such immunosuppressive strategy has been initiated at the Thomas E Starzl Transplantation Institute at the University of Pittsburgh Medical Center (USA) based on the therapeutic principles of recipient pretreatment and the minimal use of post-transplant immunosuppression by customising the timing and dosage of immunosuppression.
In the first 82 patients using this approach, overall immune responsiveness was reduced during the several hours preceding kidney, liver, pancreas or intestinal transplantation by administration of approximately 5mg/kg of antilymphoid globulin (Thymoglobulin). Post-transplant treatment was restricted to the calcineurin inhibitor tacrolimus, unless additional agents were temporarily required to treat breakthrough rejection. This immunosuppressive strategy promoted the elimination of the weakened donor-specific immune response induced by transplantation. Weaning from tacrolimus monotherapy after four months was performed by spacing doses to every other day or longer intervals. Patient and graft survivals were 95% and 89%, respectively, with virtually no immunosuppression-associated morbidity. The ability to wean these patients from immunosuppression has been attributed to the induction and maintenance of tolerance.(4)
Immunosuppressive compounds and therapies under investigation
New transplant compounds and therapies that are under preclinical and clinical investigation can be organised into four categories based on the mode of therapy: small-molecule inhibitors, modulators of lymphocyte circulation, tolerance-inducing agents and genes (see Table 1).(5)
More immunosuppressive drugs than ever have recently moved from the laboratory to clinical trials for their safety and efficacy in transplant patients. None is perfect, but they do control different forms of rejection in stringent animal models more effectively than other immunosuppressants. These novel molecules suppress the immune system far more specifically than steroids and regimens that cause lymphopenia. Not only do these new drugs block different biochemical steps that normally lead to fully functional T- and B-cells after stimulation with alloantigen, but their toxicity profiles also differ. Results from preclinical studies predict the use of selected combinations of these drugs will be more effective, less nephrotoxic, less myelotoxic and less broadly immunosuppressive than current regimens based on ciclosporin, T-cell depletion, steroids or azathioprine. The addition of these compounds will give transplant providers increased opportunity to better fit their immunosuppressive regimens to their centre and their patients.(6) However, the degree of benefit will likely exist between these two extremes: immunosuppressive regimens that are safer and better tolerated by patients yet offer equal or improved efficacy.
Graft survival, safety, side-effects, cost and ease of use are all areas where advancements in drug development are still possible and are being actively pursued. Many laboratories throughout the world are studying new, emerging compounds and therapies that may offer benefits in transplantation. A number of these compounds will be studied in animal transplant models, where they will demonstrate promise and move into human clinical trials. From these investigations, a few will become silver bullets against organ rejection in the future.
- Organ Procurement and Transplantation Network. Data as of 3 February 2003. Available from: URL: www.optn.org/latestdata
- Norman DJ, Turka LA. Primer on transplantation. Mt Laurel (NJ): American Society of Transplantation; 2001.
- Goddard S, Adams DH. New approaches to immunosuppression in liver transplantation. J Gastroenterol Hepatol 2002;17:116-26.
- Starzl TE, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003;364(9368):1502-10.
- Schmouder RL. Immunosuppressive therapies for the twenty-first century. Transplant Proc 2000;32:1463-7.
- Morris RE. Immunosuppressive drugs: mechanisms of action [abstract]. International Congress of Immunosuppressive Drugs, Minneapolis, USA. August 1995. Available from: URL: www.sat.org.ar/revista/abstract/al-3h18.htm