Chronic diseases often lead to fibrosis, a condition in which organ tissues experience 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 is found to also work in humans, it could lead to an effective treatment for fibrosis.
Fibrosis is a pathological proliferation of connective tissue that destroys the tissues of an organ. It’s the end result of almost every type of chronic damage. Fibrosis can occur in nearly every type of tissue in the body, although the liver, lungs, heart, and kidneys are most often affected. Fibrosis is responsible for up to 45 percent of all deaths in industrialized countries. Inflammation or vascular disorders often cause chronic organ damage. They activate fibroblasts, which then begin to multiply uncontrollably and form deposits of fibrous tissue. This leads to scarring of the tissues of the organ, destroying them little by little. The affected organ’s performance worsens significantly until it fails completely.
Eliminate activated fibroblasts while leaving resting cells undamaged
An international research team led by the University of Zurich (UZH) has developed a new strategy to eliminate fibroblasts in a targeted manner.
In animals, we were able to induce an immune response similar to that of vaccination, in which activated connective tissue cells were destroyed while fibroblasts were left in a resting state unharmed.”
Christian Stockmann, Study Leader, 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 at the same time leaving healthy tissue unharmed.
The difference in surface structures was determined
This is where previous strategies to treat fibrosis have previously failed, because they also damaged fibroblasts at rest. Resting fibroblasts are important, however, for maintaining the structure and functioning of healthy tissue. So the researchers studied the differences between resting surfaces and activated connective tissue cells. “Our computer-aided analyzes revealed that fragments of two surface proteins – Adam12 and Gli1 – that the immune system can detect, are present in high numbers on activated fibroblasts, while very few are present on resting cells,” Stockmann explains. The activity of these two protein genes is stimulated by chronic tissue damage, which means that activated fibroblasts produce said proteins in greater amounts.
Immunotherapy reduces lung and liver fibrosis in mice
The researchers then used these two surfactants as a vaccine in mice in order to stimulate an immune response via cytotoxic T cells. These immune cells usually kill virus-infected cells or cancer cells. “Through newly developed immunotherapy, we were able to efficiently eliminate fibroblasts in mice, thereby reducing fibrosis in the liver and lungs, without affecting healthy organ tissues,” Stockmann says. If scientists succeed in eliciting a comparable targeted immune response in humans, vaccine-based immunotherapy could be used in the future to treat patients with organ fibrosis.
Sobeki, M.; et al. (2022) Vaccination-based immunotherapy to target fibrotic cells in the liver and lung. Stem cell cells. doi.org/10.1016/j.stem.2022.08.012.