Overcoming Transplant Rejection
Aug 18, 2017 Cedars-Sinai Staff
The body is hardwired to repel invaders, and when it receives an organ transplant, the immune system goes into overdrive trying to expel it. That’s why transplant patients take immunosuppressant drugs for the rest of their lives. The drugs work well—so well that patients can end up in a Catch-22: If the immune system is successfully weakened, the body stops trying to reject the new organ but becomes vulnerable to serious diseases, including cancer and cardiovascular disease. Immunosuppressant drugs also can trigger side effects such as high blood pressure and kidney failure. The brightest minds in transplantation are working on this challenge.
Five experts share their ideas for overcoming transplant rejection.
Restore the PancreasMost pancreas transplants are performed to treat type 1 diabetes, an autoimmune disease in which the immune system attacks the pancreas and destroys insulin-producing cells (also known as beta cells). Without insulin, blood sugar levels rise to dangerous levels. "We can transplant the pancreas, but the surgery is reserved mainly for those with kidney failure from diabetes who need a kidney transplant at the same time. The risks of such complex surgery can be serious," Dr. Donald C. Dafoe says.
Fortunately, he adds, "there may be a better approach." Using induced pluripotent stem cells, he and his team grew healthy beta cells and injected them into diabetic mice. The result? The transplanted cells started producing insulin. These insulin-producing cells could be generated from a specific patient’s own skin cells, thereby avoiding rejection. If the experimental technology works, "future patients may still need to take immunosuppressant drugs due to recurrent autoimmune attack—but hopefully at far lower doses and with fewer side effects."Dr. Donald C. Dafoe is the former director of the Pancreas Transplant Program in the Cedars-Sinai Comprehensive Transplant Center. His research focuses on islet and pancreas transplantation in the treatment of diabetes mellitus. He also is investigating the growth and development of insulin-producing cells from embryonic stem cells.
Require Insurance Companies to Cover Sensitized Patients
Some transplant patients need a little extra help. If they've been pregnant, had blood transfusions, or had a previous transplantation, their blood has developed antibodies that make it incompatible with most donated organs. Only about 10% of such patients can receive a transplant. Treatment with intravenous gamma globulin (IVIG) raises that number to 35% and, if IVIG is combined with the drug rituximab, the compatible patients figure rises to 80%. IVIG therapy was first adapted for use in transplantation by researchers led by Dr. Stanley C. Jordan, medical director of the Comprehensive Transplant Center's Kidney Transplant Program.
"The problem is that some payers do not cover desensitization treatments, and that should change," says Ashley Anh Vo, PharmD. One year of dialysis costs around $85,000. By contrast, annual transplant costs after the first year are $19,000. "Paying for desensitization therapies would actually save money."Ashley Anh Vo, PharmD is the administrative director of the Transplant Immunotherapy Program at the Cedars-Sinai Comprehensive Transplant Center.
Give Doctors Time to Run Crucial Tests
In an ideal world, every donated heart would be matched perfectly to a waiting patient. The reality is more challenging. "Since a heart is only viable for a few hours after being removed from a donor," Dr. Czer says, "there is not enough time to coordinate the HLA matching, which is based on the HLA blood test in the patient and in the donor." An HLA test looks for human leukocyte antigen to reveal whether the patient and donor are well-matched.
For kidneys, doctors have approximately 24 hours to coordinate HLA matching between patient and donor. "For the heart, we're forced to rely only on blood type and body size," Dr. Czer says. The HLA test must be conducted later, when the heart is already in the patient, to determine how much immunosuppressant medication will be needed. Keeping the heart viable longer could potentially allow enough time for HLA matching between each donor and patient.Dr. Lawrence S. Czer is medical director of the Heart Transplant Program and associate medical director of the Mechanical Circulatory Support Program. His areas of expertise include transplantation, cardiomyopathy, congestive heart failure, immunotherapy, and myocarditis.
Make Aftercare Easier On PatientsOn Dec. 5, 2002, a pastor read Michael Adams his last rites. Adams had been waiting for two new lungs, but hope was fading. Before nightfall, his fortunes changed. He received a call telling him that new lungs were available for him. The surgery at Cedars-Sinai took place the next day.
More than 14 years later, Adams is alive—and deeply grateful. While he has no true complaints, and sings the praises of his surgical team, he hopes one thing will change. "The amount of medication we need can feel overwhelming," he says of the drugs that stop his body from rejecting the donated lungs. "I will likely have to take 20 different drugs every day for the rest of my life. If they could find a way to condense those drugs into fewer pills, it would ease some of the challenges of living with a transplanted organ."Michael Adams, a lung transplant recipient, lives in San Diego, where he frequently speaks in schools and hospitals on the importance of organ and tissue donation.
Convince the Body to Accept the New Organ
The body tries to reject a donated organ because it does not recognize it as part of itself. "If we can convince the body that the new organ belongs there, we'll conquer one of the biggest problems in transplant medicine," says Xiaohai Zhang, PhD. One way is to inhibit expression of certain genes in the recipient. Zhang wants to take the research to the next level, focusing on not only the recipient but also the donor.
"Using a revolutionary gene-editing technique called CRISPR-Cas9, we can do something that was impossible just a few decades ago: We can change the way a gene behaves," he says. "I believe we can stop donated organs from expressing the genes that throw the recipient's immune system into overdrive." He notes that the technology is in its infancy, but it's shown a lot of promise in animal models. "We'll get there," Zhang says.Xiaohai Zhang, PhD, is a diplomate of the American Board of Histocompatibility and Immunology, is director of the HLA and Immunogenetics Laboratory at Cedars-Sinai's Comprehensive Transplant Center.
Read more on innovations in transplant medicine:Overcoming Obstacles in Organ Transplantation Could Organ Transplantation Become a Thing of the Past?
This article is re-published from Discoveries magazine, which covers medical research at Cedars-Sinai and its impact on patient care.