Chronic diseases often lead to fibrosis, a condition in which organic tissue suffers from excessive scarring. Researchers at the University of Zurich have now developed an immunotherapy that specifically targets the cause – activated fibroblasts – while leaving normal connective tissue cells unharmed. If this approach also proves effective in humans, it could lead to an effective treatment for fibrosis.
Fibrosis is a pathological proliferation of connective tissue that destroys organic tissue. It is the ultimate consequence of almost all types of chronic damage. Fibrosis can occur in almost any type of tissue in the body, although the liver, lungs, heart, and kidneys are most commonly affected. Fibrosis is responsible for up to 45% of all deaths in industrialized countries. Inflammation or vascular disorders often cause chronic organ damage. They activate the fibroblasts, which then begin to proliferate uncontrollably and create deposits of fibrous tissue. This scars the organic tissue, destroying it little by little. The functioning of the affected organ noticeably worsens until it completely fails.
Eliminate activated fibroblasts while leaving resting cells intact
An international research team led by the University of Zurich (UZH) has now developed a new strategy to eliminate fibroblasts in a targeted manner.
In animals, we were able to elicit a vaccination-like immune response, in which activated connective tissue cells were destroyed while resting fibroblasts were undamaged.”
Christian Stockmann, Study Director, Professor, Institute of Anatomy, University of Zurich
In this way, the researchers were able to reduce fibrosis in vital organs such as the liver and lungs while leaving healthy tissue unharmed.
Difference in identified surface structures
This is where previous fibrosis treatment strategies had failed, as they also damaged resting fibroblasts. However, resting fibroblasts are important for maintaining healthy tissue structure and function. The researchers therefore studied the differences between the surfaces of resting and activated connective tissue cells. “Our computer-assisted analyzes revealed that fragments of two surface proteins – Adam12 and Gli1 – which can be detected by the immune system, are present in large numbers on activated fibroblasts, while there are very few on resting cells,” says Stockmann. The activity of these two protein genes is stimulated by chronic tissue damage, which means that activated fibroblasts produce said proteins in greater quantities.
Immunotherapy reduces lung and liver fibrosis in mice
The researchers then used these two surface structures as a vaccine in mice to trigger an immune response via cytotoxic T lymphocytes. These immune cells normally eliminate virus-infected or cancerous cells. “Using the newly developed immunotherapy, we were able to effectively eliminate fibroblasts in mice, thereby reducing fibrosis in the liver and lungs, without affecting healthy organ tissues,” says Stockmann. If scientists can successfully elicit a comparable, targeted immune response in humans, then vaccine-based immunotherapy could be used in the future for the treatment of patients with organ fibrosis.
Sobecki, M. et al. (2022) Vaccination-based immunotherapy to target profibrotic cells in liver and lung. Cell Stem Cell. doi.org/10.1016/j.stem.2022.08.012.