T-Cells Can Help Fight Graft-vs-Host Disease

Patients given bone marrow transplants to treat cancers of the blood, such as leukemia and lymphoma, or to treat congenital immune deficiency diseases and aplastic anemia, are often afflicted with a debilitating and sometimes lethal immune response known as graft-vs-host disease. In this condition, while some cells in donor bone marrow go to work to defeat disease, others actually attack - to a devastating effect - the body of the recipient, or host.

Led by Robert L. Truitt, PhD, Professor of Pediatrics, researchers at the Medical College of Wisconsin MACC Fund Research Center have identified a type of T-lymphocyte (one kind of white blood cell) that turns off immune responses. They are working on a method of using these "regulatory T-cells" to prevent graft-vs-host disease in cancer and other diseases.

"Normally," said Dr. Truitt, "when you transplant an organ like a kidney or lung, you have to suppress the immune response of the recipient to tissue antigens on the grafted organ to prevent rejection. When you do a bone marrow transplant, it's just the opposite. Lymphocytes in the donor bone marrow react against the host. You're actually transplanting cells from the donor's immune system, and these cells may actually 'reject' the body they are put into.

"Graft-vs-host disease is like a whole-body immune response against the marrow recipient. The graft literally can attack the host. If left unchecked, this complication is debilitating at best and lethal at its worst. The good news is that we can control it now. We know what causes it, we know how to manage it, but it still develops in some patients."

Cells of the immune system are needed to fight off infectious agents, such as viruses, that are foreign to the body. When the threat has passed, the immune system must turn itself off. Specialized regulatory T-cells produced in the thymus gland help do that job, Dr. Truitt said. These same cells can prevent graft-vs-host disease, but bone marrow transplantation involves total elimination of the patient's immune system, including cells of the thymus gland. Truitt speculates that bone marrow transplant patients might not produce enough regulatory T cells after the transplant to prevent the adverse immune reaction that leads to graft-vs-host disease.

Infusion Therapy Refined
Preventing graft-vs-host disease can be accomplished by removing most of the T-lymphocytes from the original donor marrow and then infusing them into the transplant patient months later, when new regulatory T-cells have been produced in the patient's thymus and the risk for graft-vs-host reaction is lower. This procedure, known as donor lymphocyte infusion therapy, was pioneered at the Medical College by William Drobyski, MD, Professor of Medicine. Donor lymphocyte infusion has for the first time given transplant physicians a way to cure patients whose leukemia returns after a bone marrow transplant.

"Ten years ago, if a patient relapsed and the leukemia came back after they'd had a bone marrow transplant, there was not much that could be done for them," said Dr. Truitt. "That was likely the last treatment they were going to get. Dr. Drobyski started doing donor lymphocyte infusion therapies, and it worked very dramatically. He performed the procedure on about 25 patients whose leukemia had relapsed, and in many of them, it eliminated the leukemia and cured them. That development was very exciting all by itself because there were some cures with a much lower risk of graft-vs-host disease. We took the observation and moved it into the laboratory where we could study the mechanism that was at work."

Dr. Truitt and a colleague, Bryon Johnson, PhD, Associate Professor of Pediatrics, developed a mouse model to study what was going on "inside" donor lymphocyte infusion therapy. They learned that new regulatory T-cells capable of shutting down graft-vs-host immune reactions must be produced in the thymus of the host after the transplant. When a patient is prepared for a bone marrow transplant, the cells of his or her immune system, including those in the thymus, are completely wiped out, so the thymus has to be repopulated with the cells in the donor bone marrow that give rise to regulatory T-cells.

"No one had realized the importance of those cells in the transplant setting," said Dr. Truitt. "We found that the reason graft-vs-host disease was less severe when we delayed the infusion of donor lymphocytes was because the delay gave the thymus time to re-create the regulatory cells that suppress the immune response that causes graft-vs-host disease."

Timing is Everything
Since the thymus degenerates with age, older patients can be at a greater risk of developing graft-vs-host disease following bone marrow transplant because they can't produce regulatory T-cells efficiently, said Dr. Truitt. "The strategy we are now working on is to isolate those cells from the blood of the marrow donor, activate and expand them in number in the lab, and then give them to the patient much earlier after transplant," he added. "Then, we won't have to wait for the cells to develop in the patient's thymus. We might be able to infuse them right along with the marrow and prevent graft-vs-host disease from starting.

"When you're dealing with cancer, there's really a delicate balance between the anti-tumor and the anti-host effect of marrow transplantation. The same cells that kill the tumor can also kill the host, but you can't eliminate them completely because, if you do that, the leukemia is going to come back. Also, the marrow graft won't 'take' or establish itself in the new host without some of these T-lymphocytes around. So we're really dealing with a balance between opposite effects of these immune cells - one desirable, one not. Infusion of regulatory T-lymphocytes may allow us to give tumor-fighting T-cells and not worry about graft-vs-host disease."

With support from the National Institute of Health's National Heart, Lung and Blood Institute, Dr. Truitt and his team are developing their method of increasing the number of the needed cells outside the patient's body and then putting them back into patients.

Dr. Truitt said it should be possible to try the therapy on human patients within a year or two thanks to a unique clinical laboratory available at Froedtert Memorial Lutheran Hospital. Carolyn Taylor, PhD, Research Professor of Medicine, heads the Lymphocyte Propagation Laboratory where the human regulatory T-cells are being grown for use in patients.

"Dr. Taylor's lab takes our animal information and translates it back into a clinically useful protocol using human cells. The entire process related to all areas of regulatory T-cell research is a good example of how we take ideas that come out of the clinic, move them into the research lab, work on them there, then take them back into the clinic, and just keep going back and forth with developing new approaches."

Other Applications
"Another application for the administration of regulatory T-lymphocytes is in the treatment of autoimmune diseases, said Dr. Truitt. Among the possibilities are multiple sclerosis, inflammatory bowel disease (Crohn's disease), lupus, juvenile arthritis, and maybe even diabetes.

"Christopher Bredeson (MD, MS, Associate Professor) in the International Bone Marrow Transplant Registry and Health Policy Institute is interested in this possibility. He has been leading our clinical effort in using bone marrow transplantation as a treatment for multiple sclerosis. Also, David Eckels (PhD, Professor of Pediatrics) and Soumitra Ghosh (PhD, Associate Professor of Pediatrics) in the Max McGee Diabetes Center are studying regulatory T-lymphocytes in diabetes."

The same type of regulatory T-lymphocytes fail to stop unwanted immune reactions in those autoimmune diseases, Dr. Truitt said, so an overall goal of continued research would be to supply patients with functioning cells to correct the defect and turn off the body's immune response to its own tissue.

Drs. Truitt and Johnson are also working with Rimas Orentas, PhD, Assistant Professor of Pediatrics, to apply what they have learned about regulatory T-lymphocytes to understanding how immune responses to cancer are blocked. They hope that their work will lead to development of an effective cancer vaccine against neuroblastoma, a cancer of primitive nerve cells that occurs in children primarily under the age of 7. Drs. Johnson and Orentas have recently been awarded a grant from the National Cancer Institute to study the influence of regulatory T-lymphocytes on the efficacy of a tumor vaccine that is given after bone marrow transplantation.

"Regulatory T-lymphocytes are really two sides of the same "immunological coin" said Dr. Truitt. "In some settings, like bone marrow transplants and autoimmune diseases, you want them to work, but in other settings, like cancer, you want to shut them off."

Dan Ullrich
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.