By Mark Benfield, MD

The immune system is the military defense system for our body, with specialized cells and proteins that search and destroy invading organisms. Through a complex set of steps that are yet to be fully understood, the immune system develops the ability to determine normal parts of our bodies (self) from invading or damaged parts of our body (non-self).  When bacteria, viruses or other infectious agents invade, the immune system rapidly recognizes these organisms as foreign and a set of cells and proteins rapidly learn how to effectively and efficiently kill the invading organism.

After having received this special training, these cells and proteins maintain an immunologic memory so that if encountered again in the future these organisms are rapidly killed. Under normal circumstances, when we are exposed to an infectious agent for the first time, we develop an infection but our immune system rapidly develops the ability to kill these infecting organisms and the infection ends. If we encounter the same organism again, the immune system is primed and ready to kill these organisms so that a second infection with the same organism seldom occurs.

It is just this system that is so important to maintaining our health in a world full of germs that causes problems for transplant patients. When a transplanted organ is placed into a patient's body, his normal immune system recognizes the tissue as foreign, assumes it is an invading organism and begins to develop the ability to attack and kill these foreign cells. This process is transplant rejection.

In the early years of transplantation, this immune response made transplantation impossible in everyone except identical twins. However, over the past 40 years we have begun to better understand the immune processes involved in transplant rejection and many drugs have been developed to suppress these immune responses. However, a fine balance is needed to suppress the immune system enough to prevent rejection but not to allow infections.

Remarkable strides have been made in our understanding and prevention of transplant rejection. In the early days, transplant rejection was fairly uniform. However, as drugs like Corticosteroids (Prednisone) and Azathioprine (Imuran) were introduced in the 1960's, transplantation without severe rejection became possible in many people. Rejection rates remained high with 70-80 percent of patients experiencing at least one rejection episode and the one-year survival of transplanted organs at only 65 percent. The introduction of Cyclosporine (Sandimmune®, Neoral®) in the 1980's was associated with a reduction in the rate of rejection and an improvement in the one-year transplant survival to 80 percent.

Recent years have seen an explosion of medications to inhibit the immune system and stop transplant rejection including Mycophenolate mofetil (Cellcept®), Sirolimus (Rapimmune®), Tacrolimus (Prograf®), Anti-thymocyte globulin (ATGAM®, Thymoglobulin®), and anti-IL2 receptor antibodies (Zenapax®, Simulect®). With these new medications, rejection rates are as low as 10-15 percent of patients and one-year transplanted organ survival has improved to 95 percent. Although this is cause for great excitement, problems continue at both extremes of immunosuppression.

All patients' immune systems are not alike. Again, using the example of infectious diseases, with similar exposures some patients develop infections while others remain healthy. Unfortunately, our ability to measure the strength of the immune system is very limited. This makes it difficult to determine the right kind and number of medications that will effectively stop transplant rejection without causing life-threatening infections.  Because of this, some transplant patients receive too little immunosuppression while others receive too much. In patients with strong immune systems, it is likely that standard immunosuppression is inadequate to completely stop rejection. To make matters worse, as with infections, once the immune system has learned to recognize and destroy cells and tissue, the immune cells become more efficient and effective and more difficult to stop with immunosuppressive medications. This is likely why one rejection episode greatly increases the risk of further rejection episodes, chronic rejection and the eventual loss of the transplanted organ.

At the other extreme, some patients with immune systems that are easily suppressed receive more medications than they need. These patients have no transplant rejection but are at increased risk for very specific kinds of infections. Although recent transplant outcomes are excellent, we have begun to see increased frequency of infections with viruses, funguses and a very concerning disease called Post-Transplant Lymphoproliferative Disorder (PTLD).

 This balance requires constant vigilance on the part of the transplant patient and care team to assure that immunosuppression be adjusted to match the patient needs. These decisions are particularly challenging in the situation of recurrent rejection episodes. With a large number of medications available, there is almost always something else that we could try to stop rejection episodes. However, the addition of each new and stronger drug to suppress the immune system tips the balance further towards too much immunosuppression and life-threatening infections and tumors.

Unfortunately, we cannot measure this balance and often do not know that we have gone too far until the patient begins to develop complications. Further, with each rejection episode, irreversible damage is done to the transplanted kidney that often begins a cascade of events called Chronic Allograft Nephropathy (or Chronic Rejection). This is a process that we are only beginning to understand; it causes progressive scarring of the kidney and is only poorly responsive to any of the currently available medications. With recurrent rejection episodes, the immune system becomes more and more difficult to suppress requiring more potent medications. As Chronic Allograft Nephropathy develops, these drugs become less and less effective. This risk-benefit balance must be weighed by the patient and care team each time new therapeutic endeavors are considered.

The ultimate goal of all transplantation is to induce transplantation tolerance. This is the ability to manipulate the immune system in a way to confuse it into thinking that the transplanted organ is part of "self" so that no immune response is mounted, no medications are needed and no rejection occurs. This is now possible in many animal models of transplantation but is likely many years away from being possible in humans.

Mark Benfield, MD is the director of the Division of Pediatric Nephrology & Transplantation at the University of Alabama at Birmingham . In addition to coordinating the Pediatric Renal Transplantation program, he has spent many years in research of the mechanisms of immune responses in transplantation.

This article originally appeared in the September 2002 issue of aakpRENALIFE Vol. 18, No. 2.

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