September 6, 2013 | by Nicole White
If there’s a physical crossroads for cancer and diabetes at City of Hope, it’s in the laboratory of De-Fu Zeng, M.D., where researchers are finding that the two diseases have more in common than many imagine.
In fact, there may even be a common thread in their potential cures, with researchers now examining the possibility of using bone marrow transplantation – a procedure that City of Hope helped pioneer in cancer patients – to treat diabetes.
The leap is not such a big one. Already, the lab’s researchers are studying graft-versus-host disease, the ability of transplants to repair broken immune systems, and a nontoxic method of preparing the immune system for transplantation.
Though most people may associate such work with cancer, their discoveries have the potential to also affect patients with diabetes and other autoimmune conditions.
“We really are so closely linked,” said Jeremy Racine, Ph.D., a postdoctoral fellow in Zeng’s lab. “Our lab is the crossroads for these different aspects of City of Hope.”
The idea of using a bone marrow transplant – in which a patient’s immune system is essentially replaced with healthy cells either from the patient or a donor – makes conceptual sense for the treatment of diabetes, which is, at its heart, an autoimmune disease.
In diabetes, the immune system kills beta cells in the pancreas, which are responsible for regulating insulin. Although islet cell transplantation, in which beta cells are replaced with cells from a donated organ, shows promise in curing diabetes, the immune system can continue to attack the beta cells, leading to relapse.
Thus, researchers are exploring ways of using bone marrow transplantation to correct diabetics’ immune system. To do so, they must overcome some of the hurdles faced by cancer patients about to undergo bone marrow transplants.
The transplantation procedure requires the patient’s immune system to be wiped out with high doses of chemotherapy and radiation, in part to avoid rejection of the donated cells and to prevent graft-versus-host disease. In that disease, new cells attack the patient’s own tissue.
Furthermore, after a transplantation, the immune system can have difficulty fighting off bacterial and viral infections. Accepting the risk of life-threatening infection is reasonable for someone facing a deadly cancer; it’s less acceptable for type 1 diabetes.
Overcoming those challenges is how the work in Zeng’s lab becomes multipurpose. Zeng is an associate professor in the Department of Diabetes and Metabolic Diseases Research and the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope.
He's developing a nontoxic conditioning strategy that would eliminate only those cells in the immune system that pose a threat to donor cells – not the entire immune system. Using a monoclonal antibody, he aims to target a specific molecule on a specific type of T cell, one that sometimes recognizes donor cells as being foreign.
This approach could prevent graft-versus-host disease, in which donor cells recognize the patient’s tissue as being foreign and begin to attack, because it doesn't rely on traditional chemotherapy and radiation conditioning. Those therapies can spur an overwhelming immune reaction that leads to graft-versus-host disease.
Early laboratory studies have been promising, and perfecting this transplantation process would pave the way for bone marrow transplants for diabetic humans. That won’t be easy.
Perfecting the process
Patients who receive transplanted immune cells live in what’s called a mixed chimeric state, meaning that their immune systems coexsist with their donors’ immune cells. Theoretically, diabetic patients who receive a transplant early enough in their disease could regrow their own beta cells. However, those with more advanced disease would still require islet transplants.
Racine is finding that when healthy immune cells are transplanted into a diabetic subject, those immune cells re-educate the host’s immune system not to attack islet cells.
This re-education starts in an organ called the thymus, which is like a classroom in which immune cells are educated and, if necessary, disciplined. T cells pass through the thymus, and if they begin to mistake the body’s own tissue as an invader, they die. In patients with diabetes, that process is damaged. Cells that mistake the islets for invaders are allowed to live.
In his work, Racine noticed that when donor T cells entered the thymus, the defective T cells began to be killed off, just as they would be in a healthy immune system. Those cells that managed to escape the thymus continued to be re-educated in the periphery of the body by the donor cells.
However, this process requires not a matched donor – but a nonmatched donor – that is, a donor with molecules on the surface of their immune cells that are not a match for the patient. In human patients, these are called human leukocyte antigens, or HLA. In other vertebrates, this system is known as the major histocompatibility complex.
This is the opposite of what’s required for a bone marrow transplant for cancer.
Racine has observed in his laboratory that, in diabetic subjects, matched cells do not effectively reprogram the host cells and thus fail to correct the autoimmune disease. When diabetic mice were given a matched bone marrow transplant, their diabetes continued.
Furthermore, when they received an organ transplant, the new organs were rejected whether those organs were a match for the patient or for the donor. However, when diabetic mice received a mismatched bone marrow transplant, they were able to receive organs and their immune system protected them, if the new organs were a match for the marrow donor – not for the patient.
This is contrary to the current clinical practice, and indicates that autoimmune patients would require a completely different set of standards from cancer patients – as well as the nontoxic conditioning regimen being developed by Zeng.
While much of the research is early, it’s promising – not just for cancer and diabetes, but for a range of diseases that were once thought of very separately. And Racine and Zeng are at the crossroads.