Nordic Life Science 1
28 “The Nobel laureates revealed that immune tole
rance is not established only in the thymus, where immune cells are first “trained”, but that there is also a crucial second layer of control in the body’s peripheral tissues. We are now beginning to see promising developments where Tregs are being harnessed or boosted to treat autoimmune diseases.” NILS LANDEGREN characterized by the fact that they carry both CD4 on their surface (like T helper cells), and also a protein called CD25. “Sakaguchi discovered the suppressor function of a novel subpopulation of CD4+ T cells that suppressed CD8 cytotoxic effector T cells. He found that these interleukin-2 receptor alpha (CD25+) expressing cells prevent CD8+ cells from attacking the body’s own tissue and that they sustain peripheral tolerance,” explains Kjetil Taskén, Professor at the institute of Clinical Medicine at the University of Oslo and Head of the institute for Cancer Research at Oslo University Hospital. “He found that such tolerance is broken if the CD25+ cells are removed, and in elegant adoptive transfer experiments he found that transferring CD4+CD25+-depleted T cells from wild type mice to mice without T cells led to serious autoimmune manifestations, whereas transfers that also included the CD4+CD25+ cells did not. These cells were named regulatory T cells (Tregs),” explains Taskén. Scurfy mice But the scientific community needed more evidence about these new T cells, and this was provided by the other two laureates, Mary E. Brunkow and Fred Ramsdell. It all started with a mouse strain, called scurfy, affected by studies of the consequences of radiation in the 1940s (part of the Manhattan Project and the development of the atomic bomb). Some male mice were unexpectedly born with scaley and flaky skin, and an extremely enlarged spleen and lymph glands, and they lived for just a few weeks, describes the Nobel Assembly at Karolinska Institutet. Scientists found that the mutation that caused this disease was located on the mice’s X chromosome (half of all the male mice were diseased but the females could live with this mutation). I Kjetil Taskén, Professor and Head of the Cancer Research Institute, University of Oslo and Oslo University Hospital n the 1990s, researchers found that the organs of the diseased male mice were being attacked by T cells that destroyed the tissues. At this time, Brunkow and Ramsdell were working at the biotech company Celltech Chiroscience in Bothell, Washington, US, developing pharmaceuticals for autoimmune diseases. They became very interested in these scurfy mice since they thought they could provide insight into how autoimmune diseases arise. The two colleagues searched for the mutant gene, and in 2001, in Nature Genetics, they were able to show that the “Scurfy” phenotype in mice with serious autoimmune disease is due to mutations in the FoxP3 gene. “They also showed that the recessive, X-bound IPEX [Immune dysregulation, polyendocrinopathy, enteropathy X-linked] syndrome in humans that affects newborn males THE NOBEL PRIZE // MEDICINE