At a glance

◇ Granzyme B increases clinical severity in pemphigoid diseases.
◇ A topical drug that blocks the action of granzyme B was found to reduce blister formation.
◇ Granzyme B inhibitor expected to be an alternative to current steroid therapy with fewer adverse effects.

Summary

A research group led by Dr. Sho Hiroyasu and Professor Daisuke Tsuruta in the Department of Dermatology, Osaka City University Graduate School of Medicine, in collaboration with a research group led by Professor David Granville and his colleagues at the Department of Pathology and Laboratory Medicine, University of British Columbia, have shown granzyme B to be a therapeutic target for pemphigoid diseases.

Pemphigoid diseases are intractable diseases that cause itchy blisters all over the body. If untreated, they can lead to serious conditions, including death. Currently, the most common treatment is corticosteroid administration, however it may also cause critical, life-threatening adverse effects including susceptibility to bacterial and viral infections. Since the number of pemphigoid diseases are increasing within the elderly and they are more vulnerable to the adverse effects of corticosteroid, new treatment options with fewer adverse effects are a clinical need. .

In this study, the research group focused on granzyme B, which is known to be abundant near the blisters of pemphigoid, but whose role has not been studied. Using three independent animal models, they found that granzyme B increases clinical severity in pemphigoid diseases. They also found that a topical granzyme B inhibitor reduces disease severity and blistering in animal models of pemphigoid. Lastly, this study found that in human patients, granzyme B is abundant in the blister fluid and the lesions.

This study shows that a topical application of a granzyme B inhibitor (VTI-1002) treats blisters in animal models of pemphigoid diseases, and it is expected to be applicable on human patients as well.

The results of this research were published online in Nature Communications (IF = 12.121) on Tuesday, January 12 (Japan time).?

Research background

Pemphigoid diseases are diseases that causes itchy blisters all over the body. This disease is more common in the elderly and in an aging society the number of patients is increasing. If untreated, it can lead to blisters all over the body and in the worst case, death. It is known that the immune system, a mechanism that eliminates foreign entities such as viruses and bacteria that have entered the body, causes the disease by mistakenly attacking the structures that anchor the outermost skin layer (epidermis) and the deeper skin layer (dermis). For this reason, a common treatment is to use steroids and other immunosuppressive drugs to generally suppress one's immune system. However, these treatments have life-threatening adverse effects such as increased susceptibility to bacterial and viral infections. Therefore, this research group investigated the mechanisms of pemphigoid to develop a new treatment method that can replace immunosuppression.

Research content

In pemphigoid diseases, it is known that the immune system uses several types of proteases, enzymes that break down proteins, to attack of the skin structures. However, therapies targeting such proteases have not been used in the treatment of the disease due to their low efficacy and severe side effects. This research group focused on a protease called granzyme B, which is known to be abundant near the blisters of pemphigoid. Since this protease is rarely found in normal skin, they expected a treatment that inhibited it would cause almost no side effects.

Using three independent animal models, the research group found that granzyme B increases severity of pemphigoid diseases. For one, they found that granzyme B directly cleaves the structures that connects the epidermis to the dermis. In addition, they found that granzyme B is responsible for recruiting immune cells to the skin, which in turn release additional proteolytic enzymes to degrade these connecting structures. Importantly, a topical treatment that inhibits the action of granzyme B (VTI-1002) was found to treat blisters in an animal model of pemphigoid disease. Finally, they found that granzyme B increases in the fluid surrounding and in the contents of blisters in human patients.

In conclusion, this research group has shown that the topical application of granzyme B inhibitor (VTI-1002) used to treat animal models of pemphigoid may also be used on human patients.

Publication information

Journal – Nature Communications

Paper title - Granzyme B Inhibition Reduces Disease Severity in Autoimmune Blistering Diseases

Authors - Sho Hiroyasu*, Matthew R. Zeglinski, Hongyan Zhao, Megan A. Pawluk, Christopher T. Turner, Anika Kasprick, Chiharu Tateishi*, Wataru Nishie, Angela Burleigh, Peter A. Lennox, Nancy Van Laeken, Nick J. Carr, Frank Petersen, Richard I. Crawford, Hiroshi Shimizu, Daisuke Tsuruta*, Ralf J. Ludwig, and David J. Granville

*Osaka City University

Article URL - https://www.nature.com/articles/s41467-020-20604-3

DOI - 10.1038/s41467-020-20604-3

Funding

This research was supported by the Canadian Institutes for Health Research, Michael Smith Foundation for Health Research. David Granville is a co-founder, chief science officer and consultant for viDA therapiutics, Inc. which developed the granzyme B inhibitor (VTI-1002).