Chronic alcohol abuse and hepatitis can lead to severe liver damage, resulting in a condition known as liver fibrosis. This condition is characterized by the excessive accumulation of collagen and scar tissue in the liver, which impairs its normal function. While treatments for liver fibrosis are limited, researchers from the University of California San Diego School of Medicine, in collaboration with the National Cancer Institute, are exploring a groundbreaking approach. They are investigating the use of immunotoxins to target and eliminate collagen-producing cells in the liver, potentially offering a novel treatment for liver fibrosis.
In their research, they focused on a protein called mesothelin, which is not found in healthy human bodies but is produced by cancer cells and collagen-producing liver cells, known as portal fibroblasts. By designing immunotoxins that can bind to mesothelin, the researchers aimed to target and eliminate these collagen-producing cells.
Their study, published on July 12, 2021, in the Proceedings of the National Academy of Sciences, provides the first evidence that liver fibrosis may be treatable with immunotoxins designed to bind mesothelin. This innovative approach has the potential to transform the treatment landscape for liver fibrosis, a condition for which therapeutic options are currently limited.
Understanding Liver Fibrosis
Liver fibrosis is a condition characterized by the accumulation of collagen and scar tissue in the liver. It is typically the result of chronic liver injuries caused by factors such as excessive alcohol consumption and hepatitis. As the liver attempts to repair itself, the excessive deposition of collagen can lead to fibrosis, gradually compromising liver function. Advanced liver fibrosis can progress to cirrhosis, which is irreversible and often necessitates a liver transplant for survival.
Currently, treatment options for liver fibrosis are limited. Weight loss is recommended for individuals with non-alcoholic fatty liver disease, which is often associated with liver fibrosis. Alcoholic liver disease is primarily treated with corticosteroids, although their efficacy is limited. In advanced cases, liver transplantation is the only curative option, but it is only offered to a select number of patients at specialized medical centers.
Immunotoxins: A Potential Solution
Dr. Tatiana Kisseleva, the lead researcher, and her team envisioned a novel approach to target liver fibrosis at its source. They explored the use of immunotoxins, which are antibodies coupled with toxic molecules. The objective was to use these immunotoxins to selectively kill collagen-producing cells in the liver by binding to mesothelin.
The premise behind this approach is that if immunotoxins carrying toxic molecules can successfully target and bind to mesothelin, the collagen-producing cells will ingest the “gift” and subsequently perish. This strategy offers a precise and targeted way to combat liver fibrosis without harming healthy liver tissue.
Mesothelin as the Key Target
The researchers recognized that mesothelin is the key to their strategy. This protein is not naturally present in healthy human bodies but is produced by specific cells, including cancer cells and portal fibroblasts in the liver. By targeting mesothelin, the researchers could focus on the cells responsible for excessive collagen production.
Dr. Ira Pastan, a co-author of the study and an expert in using immunotoxins to target mesothelin on cancer cells, brought his expertise to this research. He has been involved in multiple clinical trials using immunotoxins to treat patients with ovarian cancer, mesothelioma, and pancreatic cancer. These trials have demonstrated the safety and potential efficacy of this approach in cancer treatment.
Developing a Suitable Model
To test the effectiveness of immunotoxins in the context of liver fibrosis, the researchers needed a suitable model. Since immunotoxins are designed to specifically recognize human mesothelin, conventional mouse models of liver fibrosis could not be used. Instead, the researchers transplanted human liver cells isolated from patients into mice. These mice were then treated with the anti-mesothelin immunotoxin.
The results were promising. In comparison to untreated mice, the immunotoxins eliminated 60 to 100 percent of human mesothelin-producing cells. Additionally, they reduced collagen deposition in the liver, highlighting the potential of this approach in treating liver fibrosis.
Expanding the Research
This groundbreaking research holds the potential to revolutionize the treatment of liver fibrosis. The current limited therapeutic options make this approach all the more significant, offering hope to individuals suffering from this condition.
Dr. Kisseleva and her team are now looking to expand their research to explore the broader applications of this strategy. Importantly, the same cells responsible for fibrosis in the liver also play a role in fibrosis in other organs, such as the lungs and kidneys. If immunotoxins targeting mesothelin can be applied successfully to these organs, it could open up new avenues for treating fibrosis in various parts of the body.
Excitingly, the safety of anti-mesothelin immunotoxins in humans has already been established through Dr. Pastan’s clinical trials in cancer treatment. This knowledge may expedite the application of this approach to address fibrosis in other areas of the body.
The innovative use of immunotoxins to target liver fibrosis by binding to mesothelin offers a promising solution to a condition with limited treatment options. Dr. Kisseleva’s research, in collaboration with Dr. Pastan, demonstrates the potential of this strategy in selectively eliminating collagen-producing cells and reducing collagen deposition in the liver.
The study’s success with transplanted human liver cells in mice is an exciting development, indicating the potential effectiveness of this approach. Moreover, the safety of immunotoxins in humans, as demonstrated in cancer trials, paves the way for future applications in treating fibrosis in other organs.
This research not only represents a potential breakthrough in liver fibrosis treatment but also sheds light on a novel strategy that could transform the treatment landscape for fibrosis in various parts of the body. The journey to finding a reliable solution for liver fibrosis has taken a significant step forward, offering hope and improved outcomes for individuals affected by this condition.