In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection

Nishimori, Asami; Konnai, Satoru; Okagawa, Tomohiro; Maekawa, Naoya; Ikebuchi, Ryoyo; Goto, Shintaro; Sajiki, Yamato; Suzuki, Yasuhiko; Kohara, Junko; Ogasawara, Satoshi; Kato, Yukinari; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1371/journal.pone.0174916

Cited by 33 publications

(44 citation statements)

References 63 publications

(72 reference statements)

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“…Recently, we established an anti-bovine PD-L1 rat-bovine chimeric antibody, and clinical study was conducted in BLV infection. Interestingly, the tested calf indicated that the proliferation of anti-BLV-specific CD4 þ T cells was increased by the chimeric antibody inoculation, while BLV provirus loads were significantly reduced, clearly demonstrating that this treatment induced antivirus activities [30]. The current results also suggest that blockade of the PD-1/ PD-L1 pathway might be an effective method for controlling bovine mycoplasmosis.…”

Section: Immunosuppression Via Pd-1/pd-l1 In Bovine Mycoplasmosissupporting

confidence: 55%

Increase of cells expressing PD‐1 and PD‐L1 and enhancement of IFN‐γ production via PD‐1/PD‐L1 blockade in bovine mycoplasmosis

Goto

Konnai

Okagawa

et al. 2017

Immunity Inflam & Disease

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IntroductionBovine mycoplasma, chiefly Mycoplasma bovis, is a pathogen that causes pneumonia, mastitis, arthritis, and otitis media in cattle. This pathogen exerts immunosuppressive effects, such as the inhibition of interferon production. However, the mechanisms involved in bovine mycoplasmosis have not been fully elucidated. In this study, we investigated the role of the programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) pathway in immunosuppression in bovine mycoplasmosis.MethodsIn the initial experiments, we used enzyme‐linked immunosorbent assay to measure interferon‐γ (IFN‐γ) from peripheral blood mononuclear cells (PBMCs) isolated from cattle with mycoplasmosis.ResultsExpectedly, IFN‐γ production significantly decreased in cattle with mycoplasmosis compared with that in clinically healthy cattle. Concomitantly, flow cytometric analysis revealed that the proportions of PD‐1+CD4+ and PD‐L1+CD14+ cells significantly increased in peripheral blood of the infected cattle. Interestingly, the number of PD‐1+CD4+ and PD‐1+CD8+ T cells were negatively correlated with IFN‐γ production from PBMCs in bovine mycoplasmosis. Additionally, blockade of the PD‐1/PD‐L1 pathway in vitro by anti‐bovine PD‐1‐ and anti‐bovine PD‐L1 antibodies significantly upregulated the production of IFN‐γ from anti‐mycoplasma‐specific cells.ConclusionsThese results suggest that the PD‐1/PD‐L1 pathway could be involved in immune exhaustion of bovine mycoplasma‐specific T cells. In conclusion, our study opens up a new perspective in the therapeutic strategy for bovine mycoplasmosis by targeting the immunoinhibitory receptor pathways.

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Section: Immunosuppression Via Pd-1/pd-l1 In Bovine Mycoplasmosissupporting

confidence: 55%

Increase of cells expressing PD‐1 and PD‐L1 and enhancement of IFN‐γ production via PD‐1/PD‐L1 blockade in bovine mycoplasmosis

Goto

Konnai

Okagawa

et al. 2017

Immunity Inflam & Disease

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“…All experimental procedures were conducted following approval from the local committee for animal studies according to the Hokkaido University (17)(18)(19)(20)(21)(22)(23)(24). Written informed consent was obtained from all owners of cattle sampled in this study.…”

Section: Ethical Approvalmentioning

confidence: 99%

Upregulation of PD-L1 Expression by Prostaglandin E2 and the Enhancement of IFN-γ by Anti-PD-L1 Antibody Combined With a COX-2 Inhibitor in Mycoplasma bovis Infection

et al. 2020

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Bovine mycoplasmosis caused by Mycoplasma bovis results in pneumonia and mastitis in cattle. We previously demonstrated that the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway is involved in immune dysfunction during M. bovis infection and that prostaglandin E 2 (PGE 2 ) suppressed immune responses and upregulated PD-L1 expression in Johne's disease, a bacterial infection in cattle. In this study, we investigated the role of PGE 2 in immune dysfunction and the relationship between PGE 2 and the PD-1/PD-L1 pathway in M. bovis infection. In vitro stimulation with M. bovis upregulated the expressions of PGE 2 and PD-L1 presumably via Toll-like receptor 2 in bovine peripheral blood mononuclear cells (PBMCs). PGE 2 levels of peripheral blood in infected cattle were significantly increased compared with those in uninfected cattle. Remarkably, plasma PGE 2 levels were positively correlated with the proportions of PD-L1 + monocytes in M. bovis-infected cattle. Additionally, plasma PGE 2 production in infected cattle was negatively correlated with M. bovis-specific interferon (IFN)-γ production from PBMCs. These results suggest that PGE 2 could be one of the inducers of PD-L1 expression and could be involved in immunosuppression during M. bovis infection. In vitro blockade Goto et al.PGE 2 -Induced Immunodysfunction During Bovine Mycoplasmosis assays using anti-bovine PD-L1 antibody and a cyclooxygenase 2 inhibitor significantly upregulated the M. bovis-specific IFN-γ response. Our study findings might contribute to the development of novel therapeutic strategies for bovine mycoplasmosis that target PGE 2 and the PD-1/PD-L1 pathway.

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“…Our recent research revealed that the PD-1/PD-L1 pathway plays critical roles in immune exhaustion and disease progression in bovine chronic infections and canine malignant cancers [6–16]. Moreover, we established anti-PD-L1 and anti-PD-1 blocking antibodies for therapeutic application in cattle and dogs [13–15]. Clinical studies have confirmed the antiviral, antibacterial, and antitumoral effects of antibody treatments [13–17].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we established anti-PD-L1 and anti-PD-1 blocking antibodies for therapeutic application in cattle and dogs [13–15]. Clinical studies have confirmed the antiviral, antibacterial, and antitumoral effects of antibody treatments [13–17]. However, the blockade effect of the PD-1/PD-L1 pathway had not been tested in horses.…”

Section: Discussionmentioning

confidence: 99%

“…We found that PD-1 and PD-L1 play critical roles in immune exhaustion and disease progression in bovine chronic infections [6–10] and in canine cancers including malignant melanoma [11, 12]. Importantly, we noted that the PD-1/PD-L1 blockade enhances T-cell responses in cattle and dogs and exhibits therapeutic effects in bovine chronic infections and canine malignant melanoma [6–10, 13–17].…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

Ganbaatar

Konnai

Okagawa

et al. 2020

Preprint

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24 Programmed death-1 (PD-1) is an immunoinhibitory receptor expressed on exhausted T cells 25 during chronic illness. Interaction of PD-1 with its ligand PD-ligand 1 (PD-L1) delivers inhibitory 26 signals and impairs proliferation, cytokine production, and cytotoxicity of T cells. We reported 27 that the PD-1/PD-L1 pathway is closely associated with T-cell exhaustion and disease progression 28 in bovine chronic infections and canine tumors. Moreover, we found that blocking antibodies 29 targeting PD-1 and PD-L1 restore T-cell functions and may be used in immunotherapy in cattle 30 and dogs. However, the immunological role of the PD-1/PD-L1 pathway remains unclear for 31 chronic equine diseases, including tumors. In this study, we identified nucleotide sequences of 32 equine PD-1 (EqPD-1) and PD-L1 (EqPD-L1) and investigated the role of anti-bovine PD-L1 33 monoclonal antibodies (mAbs) against EqPD-L1 using in vitro assays. We also evaluated the 34 expression of PD-L1 in tumor tissues of equine malignant melanoma (EMM). 35The amino acid sequences of EqPD-1 and EqPD-L1 share a high identity and similarity with 36 homologs from other mammalian species. Two clones of the anti-bovine PD-L1 mAbs recognized 37 EqPD-L1 in flow cytometry, and one of these cross-reactive mAbs blocked the binding of equine 38 PD-1/PD-L1. Importantly, PD-L1 expression was confirmed in EMM tumor tissues by 39 immunohistochemistry. A cultivation assay revealed that PD-L1 blockade enhanced the 40 production of Th1 cytokines in equine immune cells.41 These results suggest that our anti-PD-L1 mAbs may be useful for investigating the expression 42 and role of the equine PD-1/PD-L1 pathway. Further research is required to discover the 43 immunological role of PD-1/PD-L1 in chronic equine diseases and elucidate a future application 44 in immunotherapy for horse. 45 Keywords: horse, PD-1, PD-L1, IFN-γ, T cells, chronic diseases, melanoma 3 46 Introduction 47 Programmed cell death-1 (PD-1) is an immunoinhibitory receptor, which is expressed on activated 48 and exhausted T cells [1]. Its ligand programmed death ligand 1 (PD-L1) is expressed on immune 49 cells, including antigen-presenting cells, and tumor cells [1]. The interaction of PD-1 and PD-L1 50 suppresses the activation signal mediated by T-cell receptors and inhibits effector functions of T 51 cells, such as cytokine production and cell proliferation [1]. This pathway is invaluable for 52 regulating excessive immune responses. In cancers, however, tumor cells utilize the suppression 53 of T cells mediated by PD-1/PD-L1 to avoid anti-tumor immune responses [1]. In human medicine, 54 the blocking antibodies targeting PD-1 or PD-L1 have been leveraged for treatment of various 55 types of cancers and resulted in remarkable outcomes with 20%-90% response rates in multiple 56 clinical trials [1].57 Equine malignant melanoma (EMM) is a common neoplasm among aged gray horses, which 58 results in dermal tumors at multiple sites [2]. A previous study reported that around 80% of aged 59 gray horses deve...

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In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection

Cited by 33 publications

References 63 publications

Increase of cells expressing PD‐1 and PD‐L1 and enhancement of IFN‐γ production via PD‐1/PD‐L1 blockade in bovine mycoplasmosis

Increase of cells expressing PD‐1 and PD‐L1 and enhancement of IFN‐γ production via PD‐1/PD‐L1 blockade in bovine mycoplasmosis

Upregulation of PD-L1 Expression by Prostaglandin E2 and the Enhancement of IFN-γ by Anti-PD-L1 Antibody Combined With a COX-2 Inhibitor in Mycoplasma bovis Infection

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

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