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Open Access

Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

Yamato Sajiki, Satoru Konnai, Tomohiro Okagawa, Asami Nishimori, Naoya Maekawa, Shinya Goto, Kei Watari, Erina Minato, Atsushi Kobayashi, Junko Kohara, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Hirofumi Takahashi, Nobuhiro Terasaki, Akira Takeda, Keiichi Yamamoto, Mikihiro Toda, Yasuhiko Suzuki, Shiro Murata and Kazuhiko Ohashi
J Immunol July 31, 2019, ji1900342; DOI: https://doi.org/10.4049/jimmunol.1900342
Yamato Sajiki
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Satoru Konnai
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Tomohiro Okagawa
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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  • ORCID record for Tomohiro Okagawa
Asami Nishimori
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Naoya Maekawa
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Shinya Goto
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Kei Watari
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Erina Minato
‡Department of Veterinary Clinical Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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  • ORCID record for Erina Minato
Atsushi Kobayashi
‡Department of Veterinary Clinical Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Junko Kohara
§Animal Research Center, Agriculture Research Department, Hokkaido Research Organization, Shintoku 081-0038, Japan;
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Shinji Yamada
¶Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Mika K. Kaneko
¶Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Yukinari Kato
¶Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Hirofumi Takahashi
‖Shibecha Branch, Kushiro Central Office, Hokkaido Higashi Agricultural Mutual Aid Association, Shibecha 088-2311, Japan;
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Nobuhiro Terasaki
‖Shibecha Branch, Kushiro Central Office, Hokkaido Higashi Agricultural Mutual Aid Association, Shibecha 088-2311, Japan;
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Akira Takeda
‖Shibecha Branch, Kushiro Central Office, Hokkaido Higashi Agricultural Mutual Aid Association, Shibecha 088-2311, Japan;
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Keiichi Yamamoto
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
#Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Osaka 536-8523, Japan;
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Mikihiro Toda
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
**New Business and International Business Development, Fuso Pharmaceutical Industries, Ltd., Osaka 536-8523, Japan;
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Yasuhiko Suzuki
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
††Division of Bioresources, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0019, Japan; and
‡‡Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 001-0019, Japan
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Shiro Murata
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Kazuhiko Ohashi
*Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
†Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan;
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Key Points

  • PGE2 induces immune exhaustion and promotes disease progression of BLV infection.

  • Dual blockade of PGE2 and PD-L1 invigorates antiviral immune response in cattle.

Abstract

Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE2, a product of cyclooxygenase (COX) 2, suppresses Th1 responses in cattle and contributes to the progression of Johne disease, a chronic bacterial infection in cattle. However, little information is available on the association of PGE2 with chronic viral infection. Thus, we analyzed the changes in plasma PGE2 concentration during BLV infection and its effects on proviral load, viral gene transcription, Th1 responses, and disease progression. Both COX2 expression by PBMCs and plasma PGE2 concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE2 concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE2 production by PBMCs. Transcription of BLV genes was activated via PGE2 receptors EP2 and EP4, further suggesting that PGE2 contributes to disease progression. In contrast, inhibition of PGE2 production using a COX-2 inhibitor activated BLV-specific Th1 responses in vitro, as evidenced by enhanced T cell proliferation and Th1 cytokine production, and reduced BLV proviral load in vivo. Combined treatment with the COX-2 inhibitor meloxicam and anti-programmed death-ligand 1 Ab significantly reduced the BLV proviral load, suggesting a potential as a novel control method against BLV infection. Further studies using a larger number of animals are required to support the efficacy of this treatment for clinical application.

Footnotes

  • This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, by Research Project for Improving Animal Disease Prevention Technologies to Combat Antimicrobial Resistance 2017–2021 FY, and by grants from the Project of the NARO, Bio-oriented Technology Research Advancement Institution (Research Program on Development of Innovative Technology 26058 BC [to S.K.] and Special Scheme Project on Regional Developing Strategy, Grant 16817557 [to S.K.]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • The online version of this article contains supplemental material.

  • Received April 1, 2019.
  • Accepted June 28, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.

This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection
Yamato Sajiki, Satoru Konnai, Tomohiro Okagawa, Asami Nishimori, Naoya Maekawa, Shinya Goto, Kei Watari, Erina Minato, Atsushi Kobayashi, Junko Kohara, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Hirofumi Takahashi, Nobuhiro Terasaki, Akira Takeda, Keiichi Yamamoto, Mikihiro Toda, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi
The Journal of Immunology July 31, 2019, ji1900342; DOI: 10.4049/jimmunol.1900342

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Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection
Yamato Sajiki, Satoru Konnai, Tomohiro Okagawa, Asami Nishimori, Naoya Maekawa, Shinya Goto, Kei Watari, Erina Minato, Atsushi Kobayashi, Junko Kohara, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Hirofumi Takahashi, Nobuhiro Terasaki, Akira Takeda, Keiichi Yamamoto, Mikihiro Toda, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi
The Journal of Immunology July 31, 2019, ji1900342; DOI: 10.4049/jimmunol.1900342
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