A special type of dendritic cell unusual for its capacity to promote the swift death of T cells appears to prevent diabetes, according to pre-clinical studies performed at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute. The researchers are now taking steps to develop a potential clinical therapy that involves a genetically engineered version of these cells, they reported at the American Transplant Congress (ATC), Transplant 2002, at the Marriott Wardman Park Hotel in Washington, D.C.
In diabetes, a patient's own immune system T cells invade and destroy the body's insulin- producing cells, the islets of Langerhans, which are located in the pancreas. Normally T cells are engaged to attack outside foreign invaders, like a transplanted organ, when antigen-presenting cells, such as dendritic cells, identify and present these foreign substances to the T cells. Dendritic cells are found in all tissue but exist in far fewer numbers than T cells, which, when stimulated to attack, also proliferate.
While most dendritic cells originate in bone marrow, the special dendritic cell the Pitt researchers discovered in previous studies of transplant tolerance originates in the liver. Moreover, instead of causing T cells to proliferate, they found that this dendritic cell, called B220+DC, caused the T cells to die, through a process called apoptosis, and at a rapid rate.
Because T cells are the main antagonists in diabetes, Lina Lu, M.D., research associate professor of surgery at the Thomas E. Starzl Transplantation Institute, and colleagues took their previous discovery of this unique cell to see if it had an impact on the progression of diabetes.
Using a type of mouse that develops diabetes within weeks of gestation, the research team treated some mice with B220+ dendritic cells while a set of control animals received no treatment at all. The mice that did not receive the treatment all developed diabetes by 20 weeks. By comparison, at 30 weeks, those that were treated with the special dendritic cell had still not developed diabetes. Half are diabetes-free at one year.
"These results are very exciting. But perhaps it may not be so feasible to develop a therapy for humans that involve cells obtained from the liver. So, in other studies we are using a gene therapy approach to see if we can give bone marrow-derived dendritic cells the same qualities as the B220+DC," explained Dr. Lu.
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In a second study presented at ATC, Dr. Lu's colleague, Linlin Ma, M.D., visiting research associate with the Starzl Institute, provided preliminary results of such work. The researchers used a molecular decoy, which they hope to patent, that was able to fool the bone marrow dendritic cell into blocking the production of the IL-12 cytokine, a hormone-like substance that cells use to communicate with each other. Because the B220+DC inhibits production of IL-12, a cytokine that normally signals T cell proliferation, the researchers wanted the bone marrow dendritic cell to do the same.
Using this modified dendritic cell, the onset of diabetes was delayed significantly. Nine of 10 mice treated with the modified cell were protected from developing diabetes up to the age of 27 weeks, while 11 of the 12 untreated mice had already developed diabetes at 20 weeks. By 31 weeks, six of the 10 treated mice developed diabetes.
"It will be important to be able to get the bone marrow dendritic cell to mimic the B220+ cell in other ways as well, before we can consider any kind of human trial. But thus far, we are very encouraged by these results," commented John J. Fung, M.D., Ph.D., Thomas E. Starzl Professor of Surgery at the University of Pittsburgh School of Medicine.
The studies involving B220+ dendritic cells are being conducted through a program project of the Juvenile Diabetes Foundation Center for Gene Therapy Approaches to Type 1 Diabetes at Children's Hospital of Pittsburgh and the University of Pittsburgh. Massimo Trucco, M.D., Hillman Professor of Pediatric Immunology at the University of Pittsburgh School of Medicine, is the center director. Dr. Fung is principal investigator of the program project that is exploring ways to improve tolerance.
Source: University of Pittsburgh Medical Center
