DANTE · Use of novel techniques to identify pathogenic versus non-pathogenic TH17 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis.

Use of novel techniques to identify pathogenic versus non-pathogenic TH17 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis.

Autoimmune diseases and cancer are crucial medical conditions of our time. Despite various fundamental therapeutic advances in recent years there is unparalleled wealth to be gained from enhancing our scientific knowledge about pathomechanisms that open doors to precision medicine and targeted therapy. Among the major breakthroughs of the last decade, which made it from the basic research laboratory bench to the patient’s bedside, are: 1) the identification of a new pro-inflammatory T helper subpopulation called Th17 cells which are linked to the pathogenesis of many autoimmune diseases and 2) the identification of regulators of the immune system, so called checkpoint molecules, which determine the functional state of T cells that are critical for the protection against cancer. However, there are case reports that therapies targeting Th17 cells in autoimmune diseases have pro-tumor effects and that therapies used to block or stimulate immune checkpoints to target cancer cells can induce autoimmune disease entities. In this project we therefore wanted to further elucidate how Th17 cells and immune checkpoints are entangled. First, we were able to uncover a completely new function of the well-known cell death receptor Fas. Independently of its function in the induction of cell death, we could show that Fas promotes the differentiation of T cells into Th17 cells by preventing the activation of an important transcription factor of a different T helper subset, Th1 cells. This finding improves our understanding of the mechanism by which Th17 cells become pathogenic. Secondly, using the cytokine Interleukin-27, which can exhibit anti-inflammatory properties and promote tumor growth, we identified two new potential immune checkpoint receptors and studied their function in the context of cancer and autoimmune diseases. GPR65 is a receptor than can sense an acid extracellular environment, which is common in areas of inflammation and in the tumor microenvironment. Without GPR65 being expressed we saw that experimental tumor growth was significantly diminished. Additionally, we detected that Th17 cells deficient of GPR65 produce significantly less pro-inflammatory, potentially autoimmune disease causing cytokines. CysLTR2 is a receptor that binds leukotrienes, known inflammatory mediators, previously linked to allergic diseases like bronchial asthma. We were able to demonstrate that deficiency of CysLTR2 protects from experimental autoimmune encephalomyelitis, a disease model resembling human multiple sclerosis. Antibodies against GPR65 and CysLTR2 could therefore, respectively used in the right setting, serve as promising targets to treat cancer or autoimmune diseases in the future.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз