The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice

Yoshida, Shota; Nakagami, Hironori; Hayashi, Hiroki; Ikeda, Yuka; Sun, Jiao; Tenma, Akiko; Tomioka, H.; Kawano, Tetsuya; Shimamura, Munehisa; Morishita, Ryuichi; Rakugi, Hiromi

doi:10.1038/s41467-020-16347-w

Cited by 91 publications

(68 citation statements)

References 30 publications

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“…C57BL/6J mice are widely used as a model for chronic melioidosis (Hodgson et al, 2013(Limmathurotsakul et al, 2015. HFD fed C57BL/6J mouse model has been previously used to study the immune responses impaired by DM in vaccine development (Haffer, 2012;Hodgson, 2013;Yoshida et al, 2020). In agreement with previous reports the mice gained weight and developed hyperglycemia and insulin resistance and showed the presence of lipid droplets in the liver within 12 weeks of HFD feeding.…”

Section: Discussionsupporting

confidence: 82%

BpOmpW Antigen Stimulates the Necessary Immune Correlates of Protection Against Melioidosis

Tomás-Cortázar

Bossi²,

Quinn

et al. 2021

Preprint

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Melioidosis is a fatal disease caused by Burkholderia pseudomallei Gram-negative bacteria. It is the causative of 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. Diabetes mellitus is the most risk factor, increasing 12-fold the susceptibility for severe disease. IFN-y responses from CD4 and CD8 T cells, but also from NK and NKT cells are necessary to eliminate the pathogen. Elucidating the immune correlates of protection of our previously described protective BpOmpW vaccine is an essential step of any vaccine before clinical trials. Thus, we immunized non-insulin resistant C57BL/6j mice and an insulin resistant C57BL/6j mouse model of Type 2 Diabetes (T2D) with BpOmpW using Sigma Adjuvant System (SAS) (treatment) or SAS only (control). Two weeks later bloods and spleens were collected and serological analysis & in vitro exposure of splenocytes to the antigen for 60 hours were performed in both controls and treatment groups to finally analyze the stained splenocytes by flow cytometry. BpOmpW induced strong antibody response, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+regulatory T cells and produced higher IFN-y; responses in CD4+, CD8+, NK and NKT cells relative to the control group in non-insulin resistant mice. T cell responses of insulin resistant mice to BpOmpW were comparable to those in non-insulin resistant mice. In addition, as a precursor to its evaluation in human studies, humanised HLA-DR and HLA-DQ transgenic mice elicited IFN-y; recall responses in an ELISPoT-based study and PBMCs from donors that were in contact to BpOmpW for seven days experienced T cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, these range of approaches used strongly indicate that BpOmpW elicits the required immune correlates of protection to combat melioidosis and bring the vaccine closer to clinical trials.

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Section: Discussionsupporting

confidence: 82%

BpOmpW Antigen Stimulates the Necessary Immune Correlates of Protection Against Melioidosis

Tomás-Cortázar

Bossi²,

Quinn

et al. 2021

Preprint

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“…The therapeutic targeting of senescence to promote healthy aging and prevent age-related diseases, otherwise known as senotherapy, has recently been attracting increasing attention [ 43 ]. Although SA-Ts are involved in the pathogenesis of metabolic disorders [ 15 ] and the autoimmune disease systemic lupus erythematosus [ 16 ], Yoshida et al recently reported that the elimination of SA-T cells using a CD153 vaccine improved glucose tolerance and insulin sensitivity [ 44 ]. In the present study, we confirmed the accumulation of SA-Ts in the salivary glands of both aged and aly/aly mice, suggesting its involvement in the common pathogenesis of age- and SS-related sialadenitis.…”

Section: Discussionmentioning

confidence: 99%

Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sjögren’s Syndrome Model Mice

Kurosawa

Shikama

Furukawa

et al. 2021

IJMS

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Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren’s syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.

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“…Several novel drugs have been explored as senolytic, including Dasatinib (D), Quercetin (Q), D+Q [213], Luteolin [214], Fisetin [215,216], Navitoclax (ABT263) [217], BCL-XL inhibitors [216], HSP90 inhibitors [212] Piperlongumine [218], RG7112 [219], O-Vanillin [219], ABT-737 [220], and CD153 Vaccine [221] and aspirin [222,223], reviewed by Robbins et al recently [224] (Figure 2).…”

Section: Senolytics and Sasp Modulatorsmentioning

confidence: 99%

Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

Chandra

Rajawat

2021

IJMS

135

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Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.

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The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice

Cited by 91 publications

References 30 publications

BpOmpW Antigen Stimulates the Necessary Immune Correlates of Protection Against Melioidosis

BpOmpW Antigen Stimulates the Necessary Immune Correlates of Protection Against Melioidosis

Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sjögren’s Syndrome Model Mice

Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

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