The drug combination effective against bovine leukemia

Scientists have succeeded in reducing levels of the bovine leukemia virus (BLV) in cows with severe infections by combining an immune checkpoint inhibitor and an enzyme inhibitor. The finding could be utilized to control other diseases in cattle, and perhaps in humans someday.

The BLV infection is a chronic viral infection affecting cows that is endemic in Japan and many other countries. At present, there is no effective vaccine or treatment. A total of 3,859 cases of bovine leukemia were reported among cattle in Japan in 2018, a 38-fold increase over 1998, posing a serious economic threat to cattle farmers.

In previous studies, the team led by Satoru Konnai of Hokkaido University demonstrated that the progression of bovine leukemia is closely related to immune suppression induced by immune checkpoint proteins such as PD-L1, and that an anti-PD-L1 antibody could effectively treat BLV-infected cows. However, the antibody alone was not effective in advanced cases with high BLV counts. Therefore, the researchers focused on prostaglandin E₂ (PGE₂), a bioactive substance which they discovered acted as an immune suppressor by upregulating PD-L1 in cows with a chronic bacterial disease called Johne’s disease.

The research team checking a cow’s condition.

In the present study published in The Journal of Immunology, the team first showed that blood PGE₂ levels increased in BLV-infected cows as the disease progressed. They also found that a COX-2 inhibitor, which blocks the production of PGE₂, activated immune response against BLV in cultured immune cells, and that combining this with the anti-PD-L1 antibody boosted the immune activation effect. Most importantly, cows administered the COX-2 inhibitor showed reduced viral loads, demonstrating its antiviral effect in the animals themselves. Administering both drugs, the COX-2 inhibitor and anti-PD-L1 antibody in combination, led to reduced viral loads in advanced stage cows.

Administering both the COX-2 inhibitor and anti-PD-L1 antibody in combination led to reduced viral loads in advanced stage BLV-infected cows. (Sajiki Y. et al., The Journal of Immunology, July 31, 2019)

“Our study showed that the drug combination has an antiviral effect in BLV-infected animals with high viral levels, which are a major source of infection on farms,” says Satoru Konnai of Hokkaido University. The researchers plan to conduct a larger verification experiment on BLV-infected cows and also study whether the drugs have any antibacterial and antiviral effects on other bovine diseases.

The study was conducted by researchers from Hokkaido University’s Faculty of Veterinary Medicine and Research Center for Zoonosis Control, Hokkaido Research Organization’s Agricultural Research Department, Tohoku University, Hokkaido Higashi Agricultural Mutual Aid Association, Fuso Pharmaceutical Industries Ltd., and other institutions.

Satoru Konnai (third from the right, top row) and his lab members.

Original article:

Sajiki Y. et al., Prostaglandin E₂ induced immune exhaustion and enhancement of anti-viral effects by anti-PD-L1 antibody combined with COX-2 inhibitor in bovine leukemia virus infection, The Journal of Immunology, July 31, 2019.

DOI: 10.4049/jimmunol.1900342

Funding:

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), the Research Project for Improving Animal Disease Prevention Technologies to Combat Antimicrobial Resistance 2017–2021FY, and the Project of the NARO, Bio-oriented Technology Research Advancement Institution (Research Program on Development of Innovative Technology, Number 26058 BC and the Special Scheme Project on Regional Developing Strategy, Grant 16817557).

Contacts:

Associate Professor Satoru Konnai

Faculty of Veterinary Medicine

Hokkaido University

Email: konnai[at]vetmed.hokudai.ac.jp

https://lab-inf.vetmed.hokudai.ac.jp/en/

Naoki Namba (Media Officer)

Institute for International Collaboration

Hokkaido University

Tel: +81-11-706-2185

Email: en-press[at]general.hokudai.ac.jp