Kristin Tarbell, Ph.D. (right) and Sayuri Yamazaki, M.D., Ph.D used dendritic cells from mice with early Type 1 diabetes to stimulate greater numbers of T suppressor cells, halting the onset of disease in the animals.
Rockefeller University researchers have for the first time demonstrated a halting of early Type 1 diabetes in mice by restoring a critical class of T cells to their normal balance.
The findings, reported in the June 7 issue of the Journal of Experimental Medicine, prove an important biological principle that could lead to prevention of Type 1 diabetes in humans: autoimmunity can be reversed if the immune system's mechanisms for tolerance — recognition and acceptance of the body's own cells — can be repaired.
Using immune system cells called dendritic cells to stimulate increased numbers of suppressor T cells, which turn off the body's immune response, the research team rescued mice from the destruction of their pancreatic islet cells that causes Type 1 diabetes. The research was led by Kristin Tarbell, Ph.D., a postdoctoral associate in Rockefeller's Laboratory of Cellular Physiology and Immunology, headed by professor and senior physician Ralph Steinman, M.D.
"You have to stop the immune system from attacking those pancreatic islet cells," says Tarbell. Otherwise, even with the possibility of islet cell transplants, the same process that destroyed the first set will destroy the second, Tarbell explains.
"Instead of silencing the attackers directly, we learned how to generate another type of cell, called a regulatory or suppressor cell, which essentially turns off the attackers. Basically, it's a numbers game, and the problem in the onset of this disease is that there are not enough of the regulatory cells that suppress the immune response against the body's insuling-producing pancreatic islet cells," says Tarbell. Putting the right number (in the case of mice, 5000 to 50,000) of regulatory T cells where they are needed arrests the onset of Type 1 diabetes in the animals.
This research used a special source of T cells from mice genetically altered to have a majority of cells directed to the islets. Now Tarbell will extend the strategy into mice with a normal repertoire to see if the dendritic cells can coax the suppressor cells — here at a much lower frequency to begin with — to expand and become active. This is a critical next step to determine if this research can be moved forward into clinical studies.
Type 1 diabetes is an autoimmune disease occurring mostly in young people before the age of 20. Shown to have a genetic underpinning, the disease develops when normal body cell markers called antigens are not recognized by the immune system as part of the body, or self. Instead, the immune system acts as if the body's own cells are foreign pathogens. The immune system's inflammatory response slowly destroys the islet cells responsible for producing insulin until the entire mass of islet cells is wiped out. The result is diabetes-uncontrolled response to the blood sugar increases that normally occur in the human and animal body. Diabetes is fatal if not treated, and even when treated, it is a chronic disease often accompanied by dire complications.
The key to understanding the rescue of islet cells is in the kinetics of the T cell response. T cells are well known as a type of "killer"cell of the immune system, that once triggered, dole out destruction to offending invaders. However, another kind of T cell is responsible for turning off or suppressing T cells that destroy, in this case, the insulin-producing beta cells of the pancreas. When suppressor cells dominate, the immune system is alerted to stand down, or tolerate, the body's own molecules and cells.
"This tolerance is literally what keeps us alive," says Steinman. "Studies in immunology have most often tried to describe immunity, as a defense against infections and tumors. If one could learn how to induce authentic immune silencing, or tolerance, it would constitute a revolution in immunology."
T cells "know" whether to attack or tolerate by biochemically tuning in to another immune system cell called the dendritic cell.
Dendritic cells, which were discovered at Rockefeller University by Steinman and his colleagues in the early 1970s, function as lookout cells that pick up antigens, evaluate them through biochemical processing, and relay messages about how to respond to other immune system cells. Through this biologically didactic process, dendritic cells can either encourage T cells to attack or to tolerate a huge variety of antigens.
"Extensive research has allowed scientist to learn that these T regulatory cells are important in suppressing some autoimmune diseases, but they haven't been paying much attention to partnering them with antigen-presenting cells like the dendritic cells," says Tarbell. "Putting the power of these two immune cell types together is helping us envision future therapies."
In the case of Type 1 diabetes, not enough T cells are getting the message from dendritic cells to be tolerant. Across the field of diabetes research, scientists don't know why this is the case. But Tarbell, Steinman and their colleagues do know that by cultivating T cells that already are tolerating, they can change the balance of T cells that will kill versus T cells that will tolerate. They do so by taking suppressor T cells out of the organism, expanding their numbers, then introducing them back into the body. Outside of the body, instructions issuing from dendritic cells also taken from the same organism generate a larger T cell suppressor population.
"This research in a mouse model of diabetes is possible due to the efforts of Sayuri Yamazaki," says Tarbell. Yamazaki is an M.D.-Ph.D. research associate also working in Steinman's laboratory. Last year, she published findings in the Journal of Experimental Medicine showing that suppressor T cells could be isolated and made to grow in large numbers using dendritic cells as the driving force. Yamazaki also is a co-author on the current publication.
"No one had ever been able to show that specific suppressor T cells could be coaxed to proliferate in vitro. Yamazaki showed that there is a population of antigen-presenting cells - the dendritic cells from bone marrow - that encourage these T cells to proliferate," says Tarbell.
Recently doctors at Pacific Northwest Research Center in Seattle have implemented a genetic screening test that helps determine the risks of a young person's developing Type 1 diabetes. Such determinations will help clinicians monitor patients at risk for disease, and in turn, spot early onset.
Screening is necessary for prevention, Tarbell explains, because "we know that if this method for restoring the balance of suppressor T cells proves effective all the way through our research and into humans, we still need to intervene before the islet cells are completely destroyed. Measuring early onset will be just as important as treating it."
"Today, there is no treatment for autoimmune disease that is specific," says Steinman. "Tarbell's and Yamazaki's research represent a completely new area of dendritic cell biology. If caught early enough, we may be able to rescue the body from failure of tolerance, or impending autoimmunity."
Steinman is Henry G. Kunkel Professor and director of Rockefeller's Christopher H. Browne Center for Immunology and Immune Diseases.
Other co-authors on this publication include Kara Olson and Priscilla Toy, both researchers at Rockefeller University.
This research was funded by the Juvenile Diabetes Research Foundation International, the National Institutes of Health and The Rockefeller University.