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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (18 April 2024) | Viewed by 10832

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Prof. Dr. Jun Imai

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Laboratory of Physiological Chemistry, Faculty of Pharmacy, Department of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunmma 370-0033, Japan
Interests: cross presentation; dendritic cell; the ubiquitin proteasome system; antigen presentation
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Prof. Dr. Shigetaka Shimodaira

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Center for Regenerative Medicine, Kanazawa Medical University Hospital, Kahoku 920-0293, Ishikawa, Japan
Interests: T cell immunology; dendritic cell; cancer vaccine; vaccination
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Special Issue Information

Dear Colleagues,

A large number of research teams in Japan from different institutions and universities are working together and studying the molecular mechanisms of immunity, immunogenetics and/or immunopathogenesis. This Special Issue of the International Journal of Molecular Sciences (IJMS) aims to rapidly publish original contributions addressing questions of importance in immunology and related fields from Japan. We welcome manuscripts conveying novel experimental findings that would advance our understanding of the molecular mechanisms of immunity, immunogenetics and/or immunopathogenesis. Manuscripts reporting the development or testing of novel therapeutics that target molecular mechanisms are likewise sought.

Prof. Dr. Jun Imai
Prof. Dr. Shigetaka Shimodaira
Guest Editors

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Published Papers (4 papers)

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Research

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12 pages, 1415 KiB

Open AccessArticle

GTS-21 Enhances Regulatory T Cell Development from T Cell Receptor-Activated Human CD4⁺ T Cells Exhibiting Varied Levels of CHRNA7 and CHRFAM7A Expression

by Masato Mashimo, Takeshi Fujii, Shiro Ono, Yasuhiro Moriwaki, Hidemi Misawa, Tetsushi Azami, Tadashi Kasahara and Koichiro Kawashima

Int. J. Mol. Sci. 2023, 24(15), 12257; https://doi.org/10.3390/ijms241512257 - 31 Jul 2023

Cited by 1 | Viewed by 1312

Abstract

Immune cells such as T cells and macrophages express α7 nicotinic acetylcholine receptors (α7 nAChRs), which contribute to the regulation of immune and inflammatory responses. Earlier findings suggest α7 nAChR activation promotes the development of regulatory T cells (Tregs) in mice. Using human CD4⁺ T cells, we investigated the mRNA expression of the α7 subunit and the human-specific dupα7 nAChR subunit, which functions as a dominant-negative regulator of ion channel function, under resting conditions and T cell receptor (TCR)-activation. We then explored the effects of the selective α7 nAChR agonist GTS-21 on proliferation of TCR-activated T cells and Treg development. Varied levels of mRNA for both the α7 and dupα7 nAChR subunits were detected in resting human CD4⁺ T cells. mRNA expression of the α7 nAChR subunit was profoundly suppressed on days 4 and 7 of TCR-activation as compared to day 1, whereas mRNA expression of the dupα7 nAChR subunit remained nearly constant. GTS-21 did not alter CD4⁺ T cell proliferation but significantly promoted Treg development. These results suggest the potential ex vivo utility of GTS-21 for preparing Tregs for adoptive immunotherapy, even with high expression of the dupα7 subunit. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Immunology in Japan)

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11 pages, 1119 KiB

Open AccessArticle

The Detection of Immunity against WT1 and SMAD4^P130L of EpCAM⁺ Cancer Cells in Malignant Pleural Effusion

by Terutsugu Koya, Yo Niida, Misa Togi, Kenichi Yoshida, Takuya Sakamoto, Hiroki Ura, Sumihito Togi, Tomohisa Kato, Jr., Sohsuke Yamada, Haruo Sugiyama, Shigeo Koido and Shigetaka Shimodaira

Int. J. Mol. Sci. 2022, 23(20), 12177; https://doi.org/10.3390/ijms232012177 - 12 Oct 2022

Cited by 3 | Viewed by 2639

Abstract

Malignant pleural effusion (MPE) provides a liquid tumor microenvironment model that includes cancer cells and immune cells. However, the characteristics of tumor antigen-specific CD8⁺ T cells have not been investigated in detail. Here, we analyzed MPE samples taken from a patient with pancreatic cancer who received a dendritic cell vaccine targeting Wilms’ Tumor 1 (WT1) antigen over the disease course (two points at MPE^1st and 2^nd, two months after MPE1^st). Epithelial cell adhesion molecule (EpCAM)⁺ cancer cells (PD-L1⁻ or T cell immunoglobulin mucin-3, TIM-3⁻), both PD-1 or TIM-3 positive CD8⁺ T cells, and CD14⁺CD68⁺CD163⁺TIM-3⁺ macrophages increased from the MPE^1st to MPE^2nd. The ratio of WT1-specific cytotoxic lymphocytes (WT1-CTLs) to MPE CD8⁺ T cells and IFN-γ secretion of WT1-CTLs were reduced with disease progression. Coincidentally, the fraction of central memory T (T_CM) of WT1-CTLs was decreased. On the other hand, CD8⁺ T cells in response to SMAD4^P130L, which is homogeneously expressed in EpCAM⁺ cancer cells, were detected using in vitro expansion with the HLA-A*11:01 restrictive SVCVNLYH neoantigen. Furthermore, the CD8⁺ T cell response to SMAD4^P130L was diminished following remarkably decreased numbers of CD8⁺ T_CM in MPE samples. In conclusion, CD8⁺ T cells responding to WT1 or SMAD4^P130L neoantigen expressed in EpCAM⁺ pancreatic cancer cells were detected in MPE. A tumor antigen-specific immune response would provide novel insight into the MPE microenvironment. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Immunology in Japan)

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16 pages, 3274 KiB

Open AccessArticle

Different In Vitro-Generated MUTZ-3-Derived Dendritic Cell Types Secrete Dexosomes with Distinct Phenotypes and Antigen Presentation Potencies

by Takuya Sakamoto, Terutsugu Koya, Misa Togi, Kenichi Yoshida, Tomohisa Kato, Jr., Yasuhito Ishigaki and Shigetaka Shimodaira

Int. J. Mol. Sci. 2022, 23(15), 8362; https://doi.org/10.3390/ijms23158362 - 28 Jul 2022

Cited by 4 | Viewed by 2504

Abstract

Human dendritic cell (DC) dexosomes were evaluated for their function and preclinical validation for vaccines. Dexosomes are small DC-secreted vesicles that contain absorbing immune signals. Vaccine manufacturing requires a significant number of monocyte-derived DCs (Mo-DCs) from donor blood; thus, Mo-DC dexosomes are expected to serve as novel materials for cancer vaccination. In this study, we characterized a potential dexosome model using immature and mature MUTZ3-derived DCs (M-imIL-4-DC, M-imIFN-DC, M-mIL-4-DC, and M-mIFN-DC) and their dexosomes (M-imIL-4-Dex, M-imIFN-Dex, M-mIL4-Dex, and M-mIFN-Dex). Despite the lack of significant differences in viability, M-mIFN-DC showed a significantly higher level of yield and higher levels of maturation surface markers, such as CD86 and HLA-ABC, than M-mIL-4-DC. In addition, M-mIFN-Dex expressed a higher level of markers, such as HLA-ABC, than M-mIL-4-Dex. Furthermore, M-mIFN-Dex exhibited a higher level of antigen presentation potency, as evaluated using a MART-1 system, than either M-imIFN-Dex or M-mIL-4-Dex. We found that M-mIFN-Dex is one of the four types of MUTZ3-derived DCs that harbor potential immunogenicity, suggesting that DC dexosomes could be useful resources in cancer immunotherapy. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Immunology in Japan)

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Review

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24 pages, 4080 KiB

Open AccessReview

bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements

by Jay Yang, Yudai Tabuchi, Riku Katsuki and Masumi Taki

Int. J. Mol. Sci. 2023, 24(4), 3525; https://doi.org/10.3390/ijms24043525 - 9 Feb 2023

Cited by 3 | Viewed by 3491

Abstract

Monoclonal antibody therapies targeting immuno-modulatory targets such as checkpoint proteins, chemokines, and cytokines have made significant impact in several areas, including cancer, inflammatory disease, and infection. However, antibodies are complex biologics with well-known limitations, including high cost for development and production, immunogenicity, a limited shelf-life because of aggregation, denaturation, and fragmentation of the large protein. Drug modalities such as peptides and nucleic acid aptamers showing high-affinity and highly selective interaction with the target protein have been proposed alternatives to therapeutic antibodies. The fundamental limitation of short in vivo half-life has prevented the wide acceptance of these alternatives. Covalent drugs, also known as targeted covalent inhibitors (TCIs), form permanent bonds to target proteins and, in theory, eternally exert the drug action, circumventing the pharmacokinetic limitation of other antibody alternatives. The TCI drug platform, too, has been slow in gaining acceptance because of its potential prolonged side-effect from off-target covalent binding. To avoid the potential risks of irreversible adverse drug effects from off-target conjugation, the TCI modality is broadening from the conventional small molecules to larger biomolecules possessing desirable properties (e.g., hydrolysis resistance, drug-action reversal, unique pharmacokinetics, stringent target specificity, and inhibition of protein–protein interactions). Here, we review the historical development of the TCI made of bio-oligomers/polymers (i.e., peptide-, protein-, or nucleic-acid-type) obtained by rational design and combinatorial screening. The structural optimization of the reactive warheads and incorporation into the targeted biomolecules enabling a highly selective covalent interaction between the TCI and the target protein is discussed. Through this review, we hope to highlight the middle to macro-molecular TCI platform as a realistic replacement for the antibody. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Immunology in Japan)

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