Stelic Discovers New Treatment Method
for Acute Liver Failure

Stelic Institute & Co., a Tokyo-based bioventure company specializing in regenerative medicine, has announced its development of a new treatment method for acute liver failure.

The Company's Stem Cell Dynamism Research Team has shown that a protein called chemokine1 CXCL102 directly affects hepatic cells, regulating their replication and proliferation. Research results demonstrated for the first time that hepatic cells possess a mechanism for attempting to repair the wide-ranging hepatic cell necrosis associated with drug-induced acute liver failure, and that anti-CXCL10 antibodies strengthen this type of self-repairing function at the in vivo level.

"Hepatic cell replication has great potential as an alternative to current methods of treating liver damage, such as transplants and cellular therapy," said Stelic chairman Hiroyuki Yoneyama. "By administering an effective dose of a specific neutralizing agent for chemokine CXCL10, and thus promoting the histological and functional repair of hepatic cells, we hope to offer a treatment that will improve the quality of life of patients who suffer from acute liver failure."

Background

The liver is an important organ that is responsible for amino acid metabolism, ammonia metabolism, and the detoxification of chemical substances. Liver damage caused by injury or poisoning, or the deterioration of liver function owing to disease, can result in serious conditions that may be life threatening in some cases. It is particularly difficult to save the lives of patients with acute liver failure caused by damage to the hepatic cells, and until now a liver transplant was considered the only treatment method capable of improving the probability of survival. The long-term use of immunosuppressants, danger of infection, high cost, scarcity of donors and unknown side effects, however, are problems that have yet to be solved, meaning that the quality of life (QOL) of patients is markedly reduced.

For these reasons, recent years have seen a rise in the development of treatment methods based on regeneration of the liver, in order to offer superior treatments to liver transplantation. Methods that are being researched include treatments to promote regeneration by using growth factors and cytokines, and treatments employing stem cells. The mechanism of action within the body of the factors first reported as inducing the regeneration of hepatic cells has yet to be fully analyzed, however, as have the factors involved in the creation of hepatic cords during the regeneration process and the maintenance of their function.

Results of Research

Stelic's Stem Cell Dynamism Research Team has shown that hepatic cord regeneration in acute liver cell damage is regulated at the in vivo level by a protein called chemokine CXCL10. The research team discovered that in chronic hepatitis B or mouse models of liver damage, CXCL10 is strongly expressed within the damaged liver, especially within hepatic cells, and worked to elucidate its action in the belief that it might play an important role in the regeneration of hepatic cells.

Initially, the research team used a mouse model of liver damage for drug-induced acute liver failure, administering a neutralizing antibody to inhibit the activity of CXCL10 in order to investigate how this would modify damage to the liver. As a result, in mice administered the anti-CXCL10 neutralizing antibody the serum alanine transferase (ALT3) level was significantly lower, and histologically too the area of necrotized hepatic cells was strikingly reduced. From this they deduced that anti-CXCL10 antibody would also result in a striking improvement in clinical findings for liver damage associated with drug-induced acute liver failure.

They then analyzed the uptake of the proliferative cell marker 5-bromo-2-deoxyuridine (BrdU4, also known as brominated deoxyuridine), with the objective of elucidating the mechanism of anti-CXCL10 antibody in hepatic regeneration, and found that the number of BrdU-positive hepatic cells increased markedly in mice administered anti-CXCL10 antibody. Immunohistological testing for type IV collagen5 also showed that hepatic cord regeneration was proceeding extremely well. Accordingly, they showed that anti-CXCL10 antibody not only promotes replication of damaged hepatic cells, but also plays a role in rebuilding functional structures in the liver.

An investigation of these results using human hepatic cell lines in vitro found that recombinant CXCL10 protein inhibits the proliferation of hepatic cells, whereas anti-CXCL10 antibody promotes it. The research team thus demonstrated that CXCL10 directly affects hepatic cells, regulating their replication and proliferation.

These results showed for the first time that hepatic cells possess a mechanism for attempting to repair the wide-ranging hepatic cell necrosis associated with drug-induced acute liver failure, and that anti-CXCL10 antibodies strengthen this type of self-repairing function at the in vivo level.

Future Possibilities

Restoring hepatic cell damage and functional impairment related to liver tissue damage is still problematic by means of today's liver transplants or cellular therapy, and has its limits. Accordingly, attempts to regenerate the liver via the promotion of hepatic cell replication is a vital issue in achieving effective treatment for liver damage. We believe that administration of an effective dose of a specific neutralizing agent for chemokine CXCL10 will offer a new treatment by means of promoting the histological and functional repair of hepatic cells.

Glossary of Technical Terms

1. Chemokine: A general name for a class of basic, heparin-binding proteins produced in the body that have chemotactic and activating effects on white blood cells (leukocytes). Their primary structure includes four conserved cysteine residues, and they are categorized into four subfamilies known as CXC, CC, C, and CX3C according to the positions of the first two cysteine residues. To date nineteen types of receptor (CXCR1-6, CCR1-10, CR1-2, and CXC3CR1) have been reported. Each receptor is uniquely expressed on a specific cell, and migration and adhesion to a specific site on an immunocompetent cell is regulated by chemokines and chemokine receptors.
2. CXCL10: A ligand of the chemokine receptor CXCR3. This molecule is involved in the migration of activated T-cells, in particular T-helper (Th1) cells, and plays a role in viral and bacterial infection, transplant rejection, autoimmune diseases, and so-called Th1-polarized disorders.
3. ALT: A marker for determining the degree of hepatic cell damage that is in widespread clinical use.
4. BrdU: A thymidine analog that is taken up into DNA during the S phase of the cell cycle. BrdU uptake experiments are therefore an effective indicator of cellular replication and proliferation.
5. 5. Type IV collagen: A protein that is the main structural constituent of basal membranes. Immunohistological staining permits investigation of the structure of hepatic cords.