Blocking CD47 Reverses the Progression of Fibrosis
Expression of the cell surface marker CD47 helps to protect cells from destruction by the immune system. It is abused by a variety of cancers, and thus blocking CD47 is the basis for a line of research into cancer therapies that might be broadly effective. Other researchers have found that this same approach might help to reduce the size of atherosclerotic plaques, so it seems that it isn't just cancerous cells in which excess CD47 is preventing beneficial destruction. Here, researchers discover that the cells making up the scar tissue of fibrosis are similarly protecting themselves with CD47, and blocking its activity causes the immune system to remove this scarring. Fibrosis is a damaging process, an age-related malfunction in the the normal progression of regeneration, and the scarring it causes in organs such as the heart and kidney degrade their proper function, contributing to decline and disease in later life. There is no effective treatment for fibrosis at the present time, which makes this research particularly exciting.
Researchers have identified a pathway that, when mutated, drives fibrosis in many organs of the body. The pathway underlies what have been considered somewhat disparate conditions, including scleroderma, idiopathic pulmonary fibrosis, liver cirrhosis, kidney fibrosis and more, the researchers found. These diseases are often incurable and life-threatening. Importantly, the researchers were able to reverse lung fibrosis in mice by administering an antibody called anti-CD47 now being tested as an anti-cancer treatment. "The variety of diseases caused by overproduction of fibroblasts has made finding a common root cause very challenging, in part because there has been no good animal model of these conditions. Now we've shown that activating a single signaling pathway in mice causes fibrosis in nearly all tissues. Blocking the CD-47 signal, which protects cancer cells from the immune system, can also ameliorate these fibrotic diseases even in the most extreme cases."
Fibrosis occurs when the body's normal response to injury goes astray. An overenthusiastic or inappropriately timed proliferation of cells called fibroblasts, which make up the connective tissue surrounding and supporting all of our organs, can lead to many devastating diseases. In a mouse model she developed, researchers found that fibroblasts were producing unusually high levels of an important signaling molecule called c-Jun. C-Jun is a transcription factor that drives the production of many proteins involved in critical cellular processes. It's been implicated in many types of human cancer. In the current study, researchers investigated c-Jun expression levels in 454 biopsied tissue samples from patients with a variety of fibrotic diseases. They found that in every case the fibroblasts from the patients with fibrosis expressed higher levels of c-Jun than did control fibroblasts collected from people with nonfibrotic conditions.
Blocking the expression of c-Jun in laboratory-grown lung fibroblasts collected from people with idiopathic pulmonary fibrosis substantially decreased the proliferation of these cells, but not of lung fibroblasts collected from people without fibrosis. Furthermore, mice genetically engineered to overexpress c-Jun in all their body's tissues developed fibrosis in nearly every organ, including lung, liver, skin and bone marrow. "We found that c-Jun overexpression and over-activation is a unifying mechanism in many types of fibrosis. But an even more exciting part of the story is the fact that we observed that the diseased, c-Jun-expressing fibroblasts are surrounded by immune cells called macrophages. This is reminiscent of what's often seen in human cancers." Over the past eight years, researchers have shown that many human cancers evade the immune system by expressing high levels of a protein called CD47 on their surfaces. Blocking this protein with an anti-CD47 antibody restores the ability of the macrophages to gobble the cancer and has proven to be a promising treatment in animal models of the disease. Anti-CD47 antibody is currently undergoing a phase-1 clinical trial in humans with advanced solid tumors.
When researchers treated mice with c-Jun-induced lung fibrosis with daily injections of anti-CD47 antibody, the animals exhibited significantly better lung function, lived longer than their peers and cleared the fibrosis. The researchers plan to investigate whether any patients in the phase-1 trial of the anti-CD47 antibody also suffered from any fibrotic conditions. If so, they are eager to learn whether they experienced any relief as a result of participating in the trial. "We have hit upon something unique in this study. We identified a highly activated pathway that causes fibrosis in many tissues in mice, and we've showed that treating the animals with an anti-CD47 antibody reverses the fibrosis. We're hopeful that this could be a potential treatment for people with many types of fibrotic conditions."