Monoclonal antibody against human Tim‐3 enhances antiviral immune response

Li, Ge; Hou, Chunmei; Dou, Shuaijie; Zhang, Jiacheng; Zhang, Yanling; Liu, Y.; Wang, Zhiding; Xiao, He; Wang, Renxi; Chen, Guojiang; Li, Yan; Feng, Jie; Shen, Beifen; Han, Gencheng

doi:10.1111/sji.12738

Cited by 8 publications

(9 citation statements)

References 56 publications

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“…Interestingly, recent work also confirmed that exhausted T cells are existent in acute viral infections, and T cells from patients in the acute phase of Ebola infection manifested with enhancing PD-1 expression but impaired IFN-γ production [23]. Moreover, blocking Tim-3 signal efficiently enhanced IFN-γ secretion from T cells following H1N1 infection model [24]. Our previous work has firstly reported that SARS-CoV-2 triggers the expression of PD-1 and Tim-3 on T cells, suggesting exhausted T cells were persistent in COVID-19 patients during SARS-CoV-2 acute infection [7].…”

Section: Discussionmentioning

confidence: 83%

Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells

Liu

Pan

et al. 2020

Clinical Infectious Diseases

129

110

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Background We previously reported that lymphocytopenia and T cell exhaustion is notable in acute COVID19 patients, especially in aged and severe cases. Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and mechanism of Tα1 supplement to COVID-19 are still unclear. Methods We retrospectively reviewed the clinical outcomes of 76 severe cases with COVID-19 admitted into two hospitals in Wuhan from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients was measured by T cell receptor excision circles (TREC). The levels of T cell exhaustion markers PD-1 and Tim-3 on CD8+ T cells were detected by flow cytometry. Results Compared with untreated group, Tα1 treatment significantly reduces mortality of severe COVID-19 patients (11.11% vs. 30.00%, p=0.044). Tα1 timely enhances blood T cell numbers in COVID-19 patients with severe lymphocytopenia (the counts of CD8+ T cells or CD4+ T cells in circulation lower than 400/μL or 650/μL, respectively). Under such conditions, Tα1 also successfully restores CD8+ and CD4+ T cell numbers in aged patients. Meanwhile, Tα1 reduces PD-1 and Tim-3 expression on CD8+ T cells from severe COVID-19 patients in comparison with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells are roughly parallel to the rise of TRECs. Conclusions Tα1 supplement significantly reduce mortality of severe COVID-19 patients. COVID-19 patients with the counts of CD8+ T cells or CD4+ T cells in circulation lower than 400/μL or 650/μL, respectively, gain more benefits from Tα1. Tα1 reverses T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 83%

Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells

Liu

Pan

et al. 2020

Clinical Infectious Diseases

129

110

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“…Surface expressed Tim‐3 on macrophages naturally mediates inhibitory signals after binding to its ligands. In this study, sTim‐3 was used to competitively inhibit the interaction between membrane Tim‐3 and its ligands 37,38,42 . We first examined the effects of Tim‐3 on the metabolic reprogramming of macrophages.…”

Section: Discussionmentioning

confidence: 99%

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2

Zhang

Hou²,

Dou³

et al. 2020

Scand J Immunol

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T cell immunoglobulin and mucin domain‐3 (Tim‐3), an immune checkpoint molecule, plays critical roles in maintaining innate immune homeostasis; however, the mechanisms underlying these roles remain to be determined. Here, we determined that Tim‐3 controls glycolysis in macrophages and thus contributes to phenotype shifting. Tim‐3 signal blockade significantly increases lactate production by macrophages, but does not influence cell proliferation or apoptosis. Tim‐3 attenuates glucose uptake by inhibiting hexokinase 2 (HK2) expression in macrophages. Tim‐3‐mediated inhibition of macrophage glycolysis and the expression of proinflammatory cytokines, tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β are reversed by HK2 silencing. Finally, we demonstrated that Tim‐3 inhibits HK2 expression via the STAT1 pathway. We have thus discovered a new way by which Tim‐3 modulates macrophage function.

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“…TIM3 has emerged as a promising target for tumor immunotherapy, and a few antibodies against TIM3 have been reported to exhibit excellent effects in enhancing antiviral immune responses, stimulating IFN-mediated anti-tumor immunity of T cells, and counteracting tumor growth [ 27 ]. Also, there are some reports on TIM3 inhibitors, but mechanisms of the action are still unclear.…”

Section: Discussionmentioning

confidence: 99%

The biologically functional identification of a novel TIM3-binding peptide P26 in vitro and in vivo

Zhong

Zhao

Wang

et al. 2020

Cancer Chemother Pharmacol

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Purpose Recent studies have shown that TIM3 plays an important role in T-cell failure, which is closely related to the resistance to anti-programmed cell death protein 1 (PD-1) treatment. However, there have been no reports on the application of peptide blockers to TIM3. In this study, we endeavored to identify the in vitro and in vivo anti-tumor activities of a TIM3-targeting peptide screened from the phage peptide library. Methods Phage display peptide library technology, surface plasmon resonance, flow cytometry, and mixed lymphocyte reaction were utilized to screen and demonstrate the bioactivities of P26, a TIM3-targeting peptide. Meanwhile, tumor growth assay was performed to evaluate the anti-tumor effect of P26. Results In terms of affinity, we demonstrated that P26 specifically binds to TIM3 at the cellular and molecular levels, which therefore blocks the interaction between TIM3 and Galectin-9 (Gal-9) and competes with Gal-9 to bind TIM3. Additionally, P26 significantly increases T-cell activity and elevates IFN-γ and IL-2 levels in a dose-dependent manner. Notably, P26 also counteracts Gal-9-mediated T-cell suppression. More importantly, P26 can inhibit growth of MC38-hPD-L1 tumor in mice. Conclusions P26, as a novel TIM3-binding peptide, has the ideal bioactivity connecting to TIM3 and the potential prospect of application in immunotherapy as an alternative or adjuvant to existing agents.

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Monoclonal antibody against human Tim‐3 enhances antiviral immune response

Cited by 8 publications

References 56 publications

Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells

Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2

The biologically functional identification of a novel TIM3-binding peptide P26 in vitro and in vivo

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