June 28, 2000 A novel subset of immune system cells has been identified that can help prevent the rejection of donor tissue in such a highly specific manner that other parts of the immune system are not affected.
A team of researchers at the Toronto General Hospital and University of Toronto have published their results in the July, 2000 edition of Nature Medicine. Led by Li Zhang, Ph.D., a Senior Staff Scientist at the Toronto General Hospital Research Institute, Multi Organ Transplant Program, and an Assistant Professor in Department of Laboratory Medicine and Pathobiology at University of Toronto, the team demonstrated in mice that particular types of T-lymphocytes (white blood cells) are able to regulate other white blood cells in the immune system called killer T-cells that attack and destroy graft tissues they recognize as foreign.
"The dream of scientists is to be able to eventually offer transplant patients a discovery that could improve the success of transplantation," explained Dr. Zhang. "I'm excited about our work because I can see the great potential for clinical use down the road. We were able to identify a way to specifically control the immune response and, for the future, this could mean better tolerated transplants and effective curbing of autoimmune diseases, all without the use of toxic and expensive medications."
`Transplant tolerance' A greater understanding of how best to ensure that organs can be transplanted successfully is a hot topic of research the world over. The essence of this work, called "transplant tolerance", is how the body's immune system can be tricked into accepting foreign tissue as its own, while still defending the body against bacteria, viruses and cancer cells. Finding the answer to this scientific problem is the Holy Grail of transplantation research. Current transplant recipients must take strong medications for the rest of their lives, which suppress the whole immune system, making them far more susceptible to infectious and malignant diseases.
Dr. Zhang began her research quest by examining mice that were given a transfusion of white blood cells from other mice. When the transfused mice were then given a skin graft from the same mice which donated the white blood cells, Dr. Zhang observed that the graft was not rejected. However, the key question remained: which white blood cells were responsible for regulating the immune response so that the graft was not rejected? The search for cells that can transfer graft tolerance from one mouse to another has been a difficult problem for decades. Nobody has been able to identity and clone such cells or characterize how they work - until now.
`Novel subset of T-cells' Dr. Zhang's team cloned T cells under various conditions and screened many T-cells to see which types had the regulatory effect. Via this detailed and painstaking process, Dr. Zhang and her team were able to identify a novel subset of T-cells called CD4-CD8- double negative regulatory T cells. Working with Dr. Zhang on this identification were post-doctoral fellows Zhu-Xu Zhang and LimingYang as well as Kevin Young, a Ph.D. student in the lab of Dr. Zhang. They found that the novel T cells express a unique combination of cell surface markers and cytokines or cell secretions that act as signals to immune cells, making them different from any previously reported subset of T-cells. The newly identified T-cells, found in the spleen of mice, are able to zero in on and kill only the T-cells that would ordinarily attack transplanted tissues
Dr. Zhang's team found that once the proper conditions are provided for CD4-CD8- cells, they will activate and proliferate and then specifically inhibit CD8+ T cells, the killer cells that attack and destroy foreign materials. During a typical immune response, a receptor or "recognition site" on the surface of killer T cells recognizes an antigen or foreign invader, and binds to it. This process activates the killer T cell to destroy the foreign material such as tissues from a donated organ.
`A kind of decoy' But when the CD4-CD8- cells are activated, they can intervene in this process to prevent the destruction of donor tissues by acting as a kind of decoy to the killer cells. Both types of cells, the CD4-CD8- cells and the killer T cells, are able to recognize and bind to the same antigen, the tissue of the foreign organ. When the CD4-CD8- cells become activated, they are able to borrow an antigen from the donor tissue, and place it on their surface. The killer T cells, in turn, recognize this foreign material on the surface of the CD4-CD8- cells, bind to it and, in the process, are destroyed. This chain reaction results in an inhibited immune response to the donor organ tissues. The donor tissue therefore remains unharmed from the killer T cells. And the rest of the immune system remains intact to fight off infections, viruses and other invaders.
"These results are exciting and will have relevance not only for transplant recipients but also for patients with autoimmune diseases, including arthritis, diabetes and inflammatory diseases of the bowel," said Dr. Gary Levy, Director of the Multi Organ Transplant Program at Toronto General Hospital, University Health Network. "The ability to modify the host's immune response without toxic immunosuppressive drugs has been a goal long sought after by immunologists and Dr. Zhang's work moves us closer to that goal."
Toronto General Hospital is a partner with the University Health Network, along with the Toronto Western Hospital and the Princess Margaret Hospital. These teaching hospitals are affiliated with the University of Toronto. Building on the strengths and reputations of each of these remarkable hospitals, the University Health Network brings together the talent, resources, technology and skills that make it an international leader in health care, research and teaching.
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