Since the first successful kidney transplant between identical twins in 1954, organ and tissue transplantation has offered hope to tens of thousands of people suffering from a wide range of conditions. Today, doctors routinely transplant more than 25 different organs and tissues as a treatment for kidney failure, Type 1 diabetes, leukemia, end-stage pulmonary disease, liver disorders, and cardiovascular disease, among other diseases.
The hope that transplantation has given to many people facing a debilitating and often fatal illness, however, has sometimes been tempered with disappointment.
Except in the rare case in which a donor is an identical twin to the recipient, transplants involve immunologic mismatches. As a result, the graft may be rejected or not function properly, or cells from the graft may attack the patient’s healthy cells. All these problems remain potential barriers to a transplant recipient resuming a normal life. In addition, transplant recipients generally must take anti-rejection drugs daily for the rest of their lives, and the drugs can themselves cause organ damage and increase susceptibility to disease, infection, and cancer.
Though the one-year survival rate after organ transplantation has improved markedly over the last 25 years, the long-term graft and patient survival rates have improved relatively little.
The Holy Grail of transplantation has always been immune tolerance: inducing the recipient’s body to accept the transplanted tissue while maintaining immunologic responsiveness to infectious agents of disease. Through the efforts of researchers affiliated with the NIAID Immune Tolerance Network (ITN), researchers are beginning to make small successes in this area.
Recently, David Sachs, M.D., a surgeon at Massachusetts General Hospital in Boston, led an experimental study that transitioned four of five kidney transplant patients from a traditional regimen of anti-rejection drugs to living without the drugs. The fifth patient rejected the organ.
This outcome was especially noteworthy because the kidneys were very close, but not perfect, immunologic matches for the recipients.
In the study, Dr. Sachs’s team used a regimen of drugs and radiation to severely weaken the immune system of the transplant patient prior to receiving the donated organ. During surgery, the patient then received not only the organ but also an infusion of bone marrow from the donor. This was followed by a course of anti-rejection drugs that were gradually reduced, depending on the patient’s condition, over the course of 9 to 14 months.
Though the immune system that renewed itself after the bone marrow transplant was initially a hybrid from both the donor and the recipient, or chimeric, over several weeks the immune system reverted to the original characteristics of the recipient while continuing to tolerate the transplanted organ.
According to their report published in January 2008, the patients in this study had lived without anti-rejection drugs for between 2 and 5.3 years.
While the findings are encouraging, this study was small scale. In addition, although the donor organs were not a perfect immunologic match, they were mismatched by only a single HLA haplotype, the set of genetic information that determines if transplanted tissue is compatible with the recipient’s immune system. Moreover, the organs were donated by living family members. Most organs come from cadavers. In such cases, the pre-transplant procedure that culminated in a bone marrow transplant is not feasible.
Despite its limitations, the study validates the concept of gradually weaning transplant patients from powerful anti-rejection drugs and allowing them to fulfill the promise of transplant surgery by leading full and healthy lives.
“We are very encouraged by our initial success in inducing tolerance across the HLA barrier, something that has been a major goal of transplant immunology for years,” notes Dr. Sachs in a Massachusetts General Hospital news release that announced the study findings. “While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced.”
Kwai T et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358(4): 353-61 (2008).
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Last Updated March 06, 2009