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Manipulating Immune Tolerance with Cellular Therapies

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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 (30 April 2022) | Viewed by 8772

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Special Issue Editors

Prof. Dr. Natalia Marek-Trzonkowska

E-Mail Website
Guest Editor

1. International Centre for Cancer Vaccine Science, University of Gdańsk, 80-822 Gdansk, Poland
2. Department of Family Medicine, Medical University of Gdańsk, 80-211 Gdańsk, Poland
Interests: T- cell based therapies; immune tolerance; Tregs; NK cells; MSCs; type 1 diabetes; lung cancer; immunotherapy; tumour markers; intercellular interactions

Dr. Anke Fuchs

E-Mail Website
Co-Guest Editor

DFG Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
Interests: regulatory T cells (Tregs); Treg based immunotherapy; graft versus host disease (GVHD)

Dr. Seda Kızılel

E-Mail Website
Co-Guest Editor

Koc University, Istanbul, Turkey
Interests: bioengineering; immunoregulation; autoimmunity

Special Issue Information

Dear Colleagues,

The last decade has been a time of intense development and advancement in cellular therapies. It was the era of harnessing regulatory T cells for treatment and prevention of graft versus host disease (GVHD), type 1 diabetes mellitus (DM1), multiple sclerosis (MS), or induction allograft tolerance. Multiple studies also focused on the immunosuppressive potential of mesenchymal stem cells (MSCs). It was suggested that aside from regenerative and immunoregulatory potential, these cells are also non-immunogenic, and thus can be used in an allogeneic setting. Over this time, we could follow the outcomes of clinical trials where MSCs or MSC derived extracellular vesicles were used for the treatment of DM1 and GVHD. The first CAR-T cell-based therapies also demonstrated impressive clinical effects and were registered. During the last decade, we paid more attention to antigen specificity of immune cells in the context of their clinical application. We also came to understand that autoimmunity and cancer are different sides of the same coin, and, thus, through manipulating the balance between immune activation and immune suppression, we can impact the outcome of autoimmune diseases, graft rejection, GVHD, and cancer.

This Special Issue is dedicated to recent progress in cellular therapies focused on the induction of immune tolerance in the context of autoimmunity, graft tolerance, or GVHD, as well as on breaking immune tolerance to cancer. This Special Issue calls for original research and reviews that address progress and current knowledge in the methods of production of cells for immune therapies, describe mechanisms of intercellular interactions that might be targets for future clinical therapies, or can be used for the elaboration of novel therapeutic approaches. Finally, we are waiting for reports of animal studies and cell-based clinical trials. This Special Issue will help us to understand the immune system and will guide future studies to optimally design cellular therapies for the treatment of human and animal diseases.

Prof. Natalia Marek-Trzonkowska
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Cellular therapy
Induction of immune tolerance
Breaking immune tolerance
Regulatory T cells (Tregs)
CAR-T cells
TILs
Mesenchymal stem cells (MSCs)
Immunotherapy
Antigen-specific T cells
Cancer
Autoimmunity

Published Papers (3 papers)

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Research

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17 pages, 4227 KiB

Open AccessArticle

Targeting Interleukin-10 Restores Graft Microvascular Supply and Airway Epithelium in Rejecting Allografts

by Shadab Kazmi, Mohammad Afzal Khan, Talal Shamma, Abdullah Altuhami, Hala Abdalrahman Ahmed, Abdullah Mohammed Assiri and Dieter Clemens Broering

Int. J. Mol. Sci. 2022, 23(3), 1269; https://doi.org/10.3390/ijms23031269 - 23 Jan 2022

Cited by 5 | Viewed by 3209

Abstract

Interleukin-10 (IL-10) is a vital regulatory cytokine, which plays a constructive role in maintaining immune tolerance during an alloimmune inflammation. Our previous study highlighted that IL-10 mediated immunosuppression established the immune tolerance phase and thereby modulated both microvascular and epithelial integrity, which affected inflammation-associated graft malfunctioning and sub-epithelial fibrosis in rejecting allografts. Here, we further investigated the reparative effects of IL-10 on microvasculature and epithelium in a mouse model of airway transplantation. To investigate the IL-10 mediated microvascular and epithelial repair, we depleted and reconstituted IL-10, and monitored graft microvasculature, airway epithelium, and associated repair proteins. Our data demonstrated that both untreated control allografts and IL-10 (−) allografts showed a significant early (d6) increase in microvascular leakiness, drop-in tissue oxygenation, blood perfusion, and denuded airway epithelium, which is associated with loss of adhesion protein Fascin-1 and β-catenin on vascular endothelial cells at d10 post-transplantation. However, IL-10 (+) promotes early microvascular and airway epithelial repair, and a proportional increase in endothelial Fascin-1, and β-catenin at d10 post-transplantation. Moreover, airway epithelial cells also express a significantly higher expression of FOXJ1 and β-catenin in syngrafts and IL-10 (+) allografts as compared to IL-10 (−) and untreated controls at d10 post-transplantation. Collectively, these findings demonstrated that IL-10 mediated microvascular and epithelial changes are associated with the expression of FOXJ1, β-catenin, and Fascin-1 proteins on the airway epithelial and vascular endothelial cells, respectively. These findings establish a potential reparative modulation of IL-10 associated microvascular and epithelial repair, which could provide a vital therapeutic strategy to facilitate graft repair in clinical settings. Full article

(This article belongs to the Special Issue Manipulating Immune Tolerance with Cellular Therapies)

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17 pages, 4150 KiB

Open AccessArticle

Molecular Determinants and Specificity of mRNA with Alternatively-Spliced UPF1 Isoforms, Influenced by an Insertion in the ‘Regulatory Loop’

by Monikaben Padariya, Robin Fahraeus, Ted Hupp and Umesh Kalathiya

Int. J. Mol. Sci. 2021, 22(23), 12744; https://doi.org/10.3390/ijms222312744 - 25 Nov 2021

Cited by 6 | Viewed by 2018

Abstract

The nonsense-mediated mRNA decay (NMD) pathway rapidly detects and degrades mRNA containing premature termination codons (PTCs). UP-frameshift 1 (UPF1), the master regulator of the NMD process, has two alternatively-spliced isoforms; one carries 353-GNEDLVIIWLR-363 insertion in the ‘regulatory loop (involved in mRNA binding)’. Such insertion can induce catalytic and/or ATPase activity, as determined experimentally; however, the kinetics and molecular level information are not fully understood. Herein, applying all-atom molecular dynamics, we probe the binding specificity of UPF1 with different GC- and AU-rich mRNA motifs and the influence of insertion to the viable control over UPF1 catalytic activity. Our results indicate two distinct conformations between 1B and RecA2 domains of UPF1: ‘open (isoform_2; without insertion)’ and ‘closed (isoform_1; with insertion)’. These structural movements correspond to an important stacking pattern in mRNA motifs, i.e., absence of stack formation in mRNA, with UPF1 isoform_2 results in the ‘open conformation’. Particularly, for UPF1 isoform_1, the increased distance between 1B and RecA2 domains has resulted in reducing the mRNA–UPF1 interactions. Lower fluctuating GC-rich mRNA motifs have better binding with UPF1, compared with AU-rich sequences. Except CCUGGGG, all other GC-rich motifs formed a 4-stack pattern with UPF1. High occupancy R363, D364, T627, and G862 residues were common binding GC-rich motifs, as were R363, N535, and T627 for the AU-rich motifs. The GC-rich motifs behave distinctly when bound to either of the isoforms; lower stability was observed with UPF1 isoform_2. The cancer-associated UPF1 variants (P533L/T and A839T) resulted in decreased protein–mRNA binding efficiency. Lack of mRNA stacking poses in the UPF1_P533T system significantly decreased UPF1-mRNA binding efficiency and increased distance between 1B-RecA2. These novel findings can serve to further inform NMD-associated mechanistic and kinetic studies. Full article

(This article belongs to the Special Issue Manipulating Immune Tolerance with Cellular Therapies)

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Review

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25 pages, 1775 KiB

Open AccessReview

What Inhibits Natural Killers’ Performance in Tumour

by Ines Papak, Elżbieta Chruściel, Katarzyna Dziubek, Małgorzata Kurkowiak, Zuzanna Urban-Wójciuk, Tomasz Marjański, Witold Rzyman and Natalia Marek-Trzonkowska

Int. J. Mol. Sci. 2022, 23(13), 7030; https://doi.org/10.3390/ijms23137030 - 24 Jun 2022

Cited by 3 | Viewed by 2597

Abstract

Natural killer cells are innate lymphocytes with the ability to lyse tumour cells depending on the balance of their activating and inhibiting receptors. Growing numbers of clinical trials show promising results of NK cell-based immunotherapies. Unlike T cells, NK cells can lyse tumour cells independent of antigen presentation, based simply on their activation and inhibition receptors. Various strategies to improve NK cell-based therapies are being developed, all with one goal: to shift the balance to activation. In this review, we discuss the current understanding of ways NK cells can lyse tumour cells and all the inhibitory signals stopping their cytotoxic potential. Full article

(This article belongs to the Special Issue Manipulating Immune Tolerance with Cellular Therapies)

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