Stem cell therapies for autoimmune hepatitis

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Abstract

Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis. Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as therapies for a variety of disorders in latest years. Hematopoietic stem cells (HSCs) were the first known adult stem cells (ASCs) and can give rise to all of the cell types in the blood and immune system. Originally, HSC transplantation was served as a therapy for hematological malignancies, but more recently researchers have found the treatment to have positive effects in autoimmune diseases such as multiple sclerosis. Mesenchymal stem cells (MSCs) are ASCs which can be extracted from different tissues, such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs interact with several immune response pathways either by direct cell-to-cell interactions or by the secretion of soluble factors. These characteristics make MSCs potentially valuable as a therapy for autoimmune diseases. Both ASC and ASC-derived exosomes have been investigated as a therapy for autoimmune hepatitis. This review aims to summarize studies focused on the effects of ASCs and their products on autoimmune hepatitis.

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Most cited references 91

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Communication by Extracellular Vesicles: Where We Are and Where We Need to Go.

Mercedes Tkach, Clotilde Théry, Beatriz Cara (2016)

In multicellular organisms, distant cells can exchange information by sending out signals composed of single molecules or, as increasingly exemplified in the literature, via complex packets stuffed with a selection of proteins, lipids, and nucleic acids, called extracellular vesicles (EVs; also known as exosomes and microvesicles, among other names). This Review covers some of the most striking functions described for EV secretion but also presents the limitations on our knowledge of their physiological roles. While there are initial indications that EV-mediated pathways operate in vivo, the actual nature of the EVs involved in these effects still needs to be clarified. Here, we focus on the context of tumor cells and their microenvironment, but similar results and challenges apply to all patho/physiological systems in which EV-mediated communication is proposed to take place.

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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

Estelle Bettelli, Yijun Carrier, Wenda Gao … (2006)

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

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The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

Lauren W. Collison, Creg J Workman, Timothy T Kuo … (2007)

Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also suppress natural immune responses to parasites and viruses as well as anti-tumour immunity induced by therapeutic vaccines. Although the manipulation of T(reg) function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by resting or activated effector CD4+ T (T(eff)) cells, and that an Ebi3-IL-12alpha heterodimer is constitutively secreted by T(reg) but not T(eff) cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T(reg) cells co-cultured with T(eff) cells, thereby boosting Ebi3 and IL-12alpha production in trans. T(reg)-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T(reg)-cell development and function. Ebi3-/- and Il12a-/- T(reg) cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3-IL-12alpha heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T(reg) cells and is required for maximal suppressive activity.

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Author and article information

Contributors

Ahmed Lotfy:

ORCID: http://orcid.org/0000-0001-9928-0724

Lotfy_bio@hotmail.com , ahmed.lotfy@psas.bsu.edu.eg

Gamal Shiha: G_shiha@hotmail.com

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 7 July 2021

Publication date PMC-release: 7 July 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 386

Affiliations

[1 ]GRID grid.411662.6, ISNI 0000 0004 0412 4932, Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), , Beni-Suef University, ; Beni-Suef, 62511 Egypt

[2 ]GRID grid.507995.7, ISNI 0000 0004 6073 8904, Department of Animal Histology and Anatomy, Faculty of Veterinary Medicine, , Badr University in Cairo (BUC), ; Cairo, Egypt

[3 ]GRID grid.13339.3b, ISNI 0000000113287408, Department of Immunology, Transplantology and Internal Diseases, , Medical University of Warsaw, ; Nowogrodzka 59, 02-006 Warsaw, Poland

[4 ]GRID grid.31451.32, ISNI 0000 0001 2158 2757, Department of Theriogenology, Faculty of Veterinary Medicine, , Zagazig University, ; Zagazig, 44511 Egypt

[5 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Department of Animal Production, College of Food and Agriculture Sciences, , King Saud University, ; Riyadh, 11451 Saudi Arabia

[6 ]GRID grid.440879.6, ISNI 0000 0004 0578 4430, Tropical Medicine Department, Faculty of Medicine, , Port Said University, ; Port Said, Egypt

[7 ]Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt

[8 ]GRID grid.10251.37, ISNI 0000000103426662, Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, , Mansoura University, ; Mansoura, Egypt

Author information

Ahmed Lotfy http://orcid.org/0000-0001-9928-0724

Article

Publisher ID: 2464

DOI: 10.1186/s13287-021-02464-w

PMC ID: 8262021

PubMed ID: 34233726

SO-VID: 782a2792-99d3-48a8-87e6-01a2fc0886b5

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 9 April 2021

Date accepted : 14 May 2021

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ScienceOpen disciplines: Molecular medicine

Keywords: stem cells,autoimmune hepatitis,mesenchymal stem cell,hematopoietic stem cells,exosomes,mesenchymal stromal cell

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ScienceOpen disciplines: Molecular medicine

Keywords: stem cells, autoimmune hepatitis, mesenchymal stem cell, hematopoietic stem cells, exosomes, mesenchymal stromal cell

Stem cell therapies for autoimmune hepatitis

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Most cited references 91

Communication by Extracellular Vesicles: Where We Are and Where We Need to Go.

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

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