A specific fragment of a protein secreted by the parasitic worm liver fluke (Fasciola) has been found to protect the articular cartilage of joints from being destroyed by the body’s aberrant immune system, thus preventing rheumatoid arthritis from progressing. Besides protecting the cartilage from further destruction, the team of researchers from the Central Drug Research Institute (CSIR-CDRI) also found that the protein prevented the joint bone from being destroyed. In rheumatoid arthritis, the joint bone starts getting destroyed following cartilage destruction.
Liver fluke secretion
Liver flukes secrete certain specialised proteins that help the parasites to evade recognition by the host immune system and also blunt the killing machinery of the immune system by dialling down the inflammatory responses.
The protein — Fasciola helminth defence molecule-1 (FhHDM-1) — secreted by liver fluke has similarity with a human protein that mitigates inflammatory responses. So the team led by Naibedya Chattopadhyay isolated a specific fragment of this protein having a high anti-inflammatory function. They then synthesised and tested it in a cell culture system followed by animal testing.
The results were published in FASEB Journal.
A mouse model that is vulnerable to rheumatoid arthritis was used for testing the protective effect of the protein. The type-II collagen protein the major component present in the cartilage matrix of the joints but not as a whole protein seen in blood was introduced in large quantities to trigger an autoimmune response. With this, the process of cartilage destruction was set in motion.
Twenty days after introducing the antigen protein to trigger an autoimmune response, the researchers introduced the synthesised peptide every second day to evaluate its potential to protect the collagen from destruction. “The peptide rapidly stopped further damage to the cartilage. The cartilage that has already been damaged was not repaired because the damage is irreversible in the case of rheumatoid arthritis,” says Yasir Akhtar Khan from the Department of Zoology at the Aligarh Muslim University, Aligarh, and the first author of the paper. “Besides preventing cartilage destruction, the peptide also prevented the joint bone from destruction.”
Action on mice
The cartilage of animals that only received the type II collagen but not the peptide was completely destroyed by the end of the experiment (46 days), while the cartilage of the treatment group that received the peptide for four weeks was protected from further damage.
The effect of treatment in controlling cartilage destruction was assessed externally during the course of treatment by measuring paw swelling every day. “By 25 days of treatment, there was complete abolition of paw swelling compared with the diseased animals that did not receive any treatment,” says Dr. Khan. All the animals were sacrificed at the end of 46 days and the joints examined.
“There was extensive structural damage to the cartilage in mice that did not receive the peptide. The barrier that insulates the cartilage was destroyed leading to disease progression,” he says. “In the treatment group, the barrier was intact and comparable to the control group that did not have rheumatoid arthritis. We also did not see any immune cells in the joints of the treated animals.”
In contrast to the currently used anti-rheumatic drug (methotrexate), the biggest advantage of using the liver fluke peptide is that it does not produce a wholesale suppression of the immune system. Even the monoclonal antibodies that act against individual inflammatory molecules have inherent problems. For instance, the monoclonal antibodies target and suppress the tumour necrosis factor (TNF alpha), which is the first line of defence against Mycobacterium. In the Indian context, the anti-rheumatic drug and even the monoclonal antibodies that target TNF alpha will leave the person susceptible to infections, including TB.
Immune system intact
“The liver fluke peptide only produces selective protection to the joints and does not alter the systemic immune system. So the body’s ability to combat bacterial pathogens will remain intact. Dr. Chattopadhyay says. “We are yet to study the mechanism of selective joint protection (cartilage and bone) provided by the peptide.”
Thus, in the Indian scenario, the peptide that specifically prevents joint inflammation and destruction without affecting the body’s overall immune function might prove a game-changer in treating rheumatoid arthritis if further tests and trials find it effective.
