Chronic alcohol abuse and hepatitis can injure the liver and lead to fibrosis, the buildup of collagen and scar tissue. As a potential approach to treating liver fibrosis, University of California San Diego (UCSD) School of Medicine researchers and their collaborators are looking for ways to stop liver cells from producing collagen.
“So we thought…what if we take immunotoxins and try to get them to kill collagen-producing cells in the liver,” said team lead Tatiana Kisseleva, MD, PhD, associate professor of surgery at UCSD School of Medicine. “If these antibodies carrying toxic molecules can find and bind the cells, the cells will eat up the ‘gift’ and die.”
In a study (“Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis”) published in PNAS, Kisseleva and colleagues say they have provided the first evidence that liver fibrosis might be treatable with immunotoxins designed to bind the protein mesothelin, which is rarely found in the healthy human body. Only cancer cells and collagen-producing liver cells, known as portal fibroblasts, make the protein.
Kisseleva teamed up with co-author Ira Pastan, MD, at the National Cancer Institute, part of the NIH. Pastan is co-discoverer of mesothelin and experienced in using immunotoxins to target the protein on cancer cells.
To test Pastan’s immunotoxins in the context of liver fibrosis, Kisseleva’s team first needed a model. Since the immunotoxins specifically recognize human mesothelin, a traditional mouse model of liver fibrosis wouldn’t work. Instead, they transplanted human liver cells isolated from patients to mice and treated them with the anti-mesothelin immunotoxin.
“We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis,” wrote the investigators.
“On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice.
“We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.”
Compared to untreated mice, 60–100% of human mesothelin-producing cells were killed by the immunotoxins, which also reduced collagen deposition.
Treatment for liver fibrosis is currently very limited. According to the NIH, weight loss is currently the only known method for reducing liver fibrosis associated with non-alcoholic fatty liver disease. Alcoholic liver disease is most commonly treated with corticosteroids, but they are not highly effective. Early liver transplantation is the only proven cure, but it is offered only at select medical centers to a limited number of patients.
“What we want to know now is, can this same strategy be applied to other organs?” Kisseleva said. “Surprisingly enough, the same cells are responsible for fibrosis in the lung and kidneys. This is especially exciting because we already know from Pasten’s cancer clinical trials that anti-mesothelin immunotoxins are safe in humans, potentially speeding up their application in other areas.”