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Autoimmune diseases in multiple organs in humans. e.g. autoimmune diseases that can co-exist in multiple tissues are: brain (multiple sclerosis), eye (autoimmune iritis and episcleritis), lung (autoimmune idiopathic pulmonary fibrosis), gut (Coeliac disease, pernicious anemia, inflammatory bowel disease), liver—autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis), kidneys (autoimmune glomerulonephritis), skin (psoriasis, pemphigus), endocrine (autoimmune thyroid disease such as Hashimoto thyroiditis, Graves' disease, type 1 diabetes, Addison's disease), and multi-organ involvement, such as systemic lupus erythematosus.
Source publication
Regulatory T cells (Tregs) are crucial in maintaining tolerance. Hence, Treg immunotherapy is an attractive therapeutic option in autoimmune diseases and organ transplantations. Currently, autoimmune diseases do not have a curative treatment and transplant recipients require life-long immunosuppression to prevent graft rejection. There has been sig...
Citations
... Future functional studies of peripheral blood and tissue-specific Tregs, particularly investigation of the influence of type I IFN on Treg suppressive capacity in JDM, would provide mechanistic insight on this population's role in disease pathogenesis. The potential translational impact of investigating Treg dysfunction is corroborated by active development of multiple therapeutics targeting Tregs for autoimmune diseases (54). ...
Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM at diagnosis. Furthermore, we find that these changes in B cells are paralleled by T cell signatures suggestive of Th2-mediated inflammation that persist despite disease quiescence. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with previously masked cell states including dysfunctional protein processing in CD4+ T cells and regulation of cell death programming in NK, CD8+ T cells and gdT cells. Together, these findings unveil the coordinated immune dysregulation underpinning JDM and provide insight into strategies for restoring balance in immune function.
... Prior to the discovery of these cell types, autoimmune disorders were characterized using the Th1/Th2 paradigm, and although Th1 and Th2 cells do play a role in autoimmune pathology, these models provide an incomplete picture of how the immune system is dysregulated [15][16][17]. Consequently, the discovery of Tregs and Th17s has revolutionized our understanding of autoimmunity and enabled the development of novel therapies such as anti-IL-17 treatments for patients with type 1 diabetes and the use of polyclonal Tregs to prevent graft-vs-host-disease during organ transplantation [18][19][20]. To this end, strict adherence to the paradigm stands as an obstacle to the development of new therapies to treat more complex conditions. ...
For decades, the Th1/2 paradigm has been used to classify immune responses as either Th1 or Th2-biased. However, in recent years, a staggering amount of evidence has emerged to support rejection of the classical Th1/Th2 paradigm, such as the discoveries of new helper T cell subsets, helper T cell plasticity and protective mixed-Th1/Th2 responses. This opinion piece investigates the shortcomings of classical Th1/Th2 paradigm in the context of recent works, with the goal of facilitating the development of newer models to represent the diversity of Th cells.
... In the past decade, there has been substantial progress in our understanding of both antigen-specific and polyclonal Tregs biology. Furthermore, clinical trials involving Tregs manufactured under strict good manufacturing practices (GMP) have revealed that Treg-based therapies are safe and exhibits early effectiveness for both organ transplants and autoimmune diseases [194,195]. ...
... These trials involve the use of GMP-sorted Tregs, specifically CD4+/CD127low/CD25high or CD4+/CD25high subsets, which are then expanded through TCR stimulation or administered via subcutaneous low-dose IL-2. To maximize the effectiveness of Treg immunotherapy, it is imperative that these cells successfully migrate to specific target tissues, maintain stability within local organs, enhance their suppressive capabilities, and ensure their continued survival while fulfilling their intended functions [194,195]. In pursuit of these objectives, the use of biomaterials emerges as a compelling and supportive strategy for augmenting Treg immunotherapy and addressing these formidable challenges [73,74,76,78,81,83,84,91,96,108]. ...
... Both systemic and organspecific autoimmune disorders are characterized by immune-mediated processes of unknown origin, stemming from disruptions in immune homeostasis. This disruption involves a lack of control over self-reactive T effector cells by Tregs, and reinstating tolerance may alleviate disease activity in affected individuals [194,196]. ...
Regulatory T cells (Tregs) are crucial for preserving tolerance in the body, rendering Treg immunotherapy a promising treatment option for both organ transplants and autoimmune diseases. Presently, organ transplant recipients must undergo lifelong immunosuppression to prevent allograft rejection, while autoimmune disorders lack definitive cures. In the last years, there has been notable advancement in comprehending the biology of both antigen-specific and polyclonal Tregs. Clinical trials involving Tregs have demonstrated their safety and effectiveness. To maximize the efficacy of Treg immunotherapy, it is essential for these cells to migrate to specific target tissues, maintain stability within local organs, bolster their suppressive capabilities, and ensure their intended function's longevity. In pursuit of these goals, the utilization of biomaterials emerges as an attractive supportive strategy for Treg immunotherapy in addressing these challenges. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for organ transplant recipients and individuals grappling with autoimmune diseases in the near future. This paper introduces strategies based on biomaterial-assisted Treg immunotherapy to enhance transplant medicine and autoimmune treatments.
... Currently, the use of cell-based drug products is the state-of-the-art method to reduce immunosuppression in organ transplantation (28). Regulatory cell therapy has emerged as an attractive therapeutic approach to establish immunomodulation aimed at protecting organ grafts (39)(40)(41). Currently, common types of regulatory cell therapy include regulatory T cells (Treg), monocyte-derived dendritic cells, and regulatory macrophages. ...
Background
Kidney transplantation is considered the most effective treatment for end-stage renal failure. Recent studies have shown that the significance of the immune microenvironment after kidney transplantation in determining prognosis of patients. Therefore, this study aimed to conduct a bibliometric analysis to provide an overview of the knowledge structure and research trends regarding the immune microenvironment and survival in kidney transplantation.
Methods
Our search included relevant publications from 2013 to 2023 retrieved from the Web of Science core repository and finally included 865 articles. To perform the bibliometric analysis, we utilized tools such as VOSviewer, CiteSpace, and the R package “bibliometrix”. The analysis focused on various aspects, including country, author, year, topic, reference, and keyword clustering.
Results
Based on the inclusion criteria, a total of 865 articles were found, with a trend of steady increase. China and the United States were the countries with the most publications. Nanjing Medical University was the most productive institution. High-frequency keywords were clustered into 6 areas, including kidney transplantation, transforming growth factor β, macrophage, antibody-mediated rejection, necrosis factor alpha, and dysfunction. Antibody mediated rejection (2019-2023) was the main area of research in recent years.
Conclusion
This groundbreaking bibliometric study comprehensively summarizes the research trends and advances related to the immune microenvironment and survival after kidney transplantation. It identifies recent frontiers of research and highlights promising directions for future studies, potentially offering fresh perspectives to scholars in the field.
... Inflammation is a series of complex pathological events initiated by infection or cell damage with non-specific attack [1]. Hyperinflammation is associated with many pathological processes of critical diseases, such as cancer [2], atherosclerosis [3,4], neurological disorder [5], Coronavirus disease 2019 (COVID-19) [6], and autoimmune diseases [7]. A cytokine storm, which is an abnormally elevated level of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, by the innate immune system, is frequently accompanied by acute hyperinflammation in patients with infectious diseases and As shown in Figure 1A, treatment of CML into HDL 3 caused a remarkable increase in the glycation extent, in a dose-dependent manner from 100 µM to 400 µM (final) during 144 h at 37 • C under 5% CO 2 , up to 29% increase in yellowish fluorescence by CML 400 µM (final) treatment than HDL 3 alone. ...
... Alternatively, adoptive transfer of CRISPR effector-specific T reg cells following ex vivo expansion can be used to induce tolerance to CRISPR therapeutics in humans. Adoptive T reg cell therapy is in clinical trials for the prevention of graft versus host disease in transplantation and the treatment of type 1 diabetes (Terry and Oo, 2020; and has been previously shown to mitigate cellular immunity in gene therapy in preclinical studies (Sarkar et al., 2014). Wagner et al. (2019) showed that SpCas9specific T reg cells suppressed effector T cells that recognize SpCas9 with suppression of cytokine production in cocultures. ...
CRISPR offers new hope for many patients and promises to transform the way we think of future therapies. Ensuring safety of CRISPR therapeutics is a top priority for clinical translation and specific recommendations have been recently released by the FDA. Rapid progress in the preclinical and clinical development of CRISPR therapeutics leverages years of experience with gene therapy successes and failures. Adverse events due to immunogenicity have been a major setback that has impacted the field of gene therapy. As several in vivo CRISPR clinical trials make progress, the challenge of immunogenicity remains a significant roadblock to the clinical availability and utility of CRISPR therapeutics. In this review, we examine what is currently known about the immunogenicity of CRISPR therapeutics and discuss several considerations to mitigate immunogenicity for the design of safe and clinically translatable CRISPR therapeutics.
... T cell mediated adaptive immune responses contribute vitally to the clearance of cancers and precancerous cells (reviewed in Refs. [1][2][3][4][5][6]), maintenance of tolerance, and induction of autoimmunity to self-antigens or transplant antigens [7][8][9][10][11][12][13][14][15]. These cells also promote the clearance of infectious agents and infection-associated cancers, post-infectious autoimmune neurological disorders, and the maintenance of viral immunity or latency [16][17][18][19][20][21][22][23][24][25][26][27]. ...
Objectives
We sought to develop medium throughput standard operating procedures for screening cryopreserved human peripheral blood mononuclear cells (PBMCs) for CD4⁺ and CD8⁺ T cell responses to potential autoantigens.
Methods
Dendritic cells were loaded with a peptide cocktail from ubiquitous viruses or full-length viral protein antigens and cocultured with autologous T cells. We measured expression of surface activation markers on T cells by flow cytometry and cytometry by time of flight 24–72 h later. We tested responses among T cells freshly isolated from healthy control PBMCs, cryopreserved T cells, and T cells derived from a variety of T cell expansion protocols. We also compared the transcriptional profile of CD8⁺ T cells rested with interleukin (IL)7 for 48 h after 1) initial thawing, 2) expansion, and 3) secondary cryopreservation/thawing of expanded cells. To generate competent antigen presenting cells from PBMCs, we promoted differentiation of PBMCs into dendritic cells with granulocyte macrophage colony stimulating factor and IL-4.
Results
We observed robust dendritic cell differentiation from human PBMCs treated with 50 ng/mL GM-CSF and 20 ng/mL IL-4 in as little as 3 days. Dendritic cell purity was substantially increased by magnetically enriching for CD14⁺ monocytes prior to differentiation. We also measured antigen-dependent T cell activation in DC-T cell cocultures. However, polyclonal expansion of T cells with anti-CD3/antiCD28 abolished antigen-dependent upregulation of CD69 in our assay despite minimal transcriptional differences between rested CD8⁺ T cells before and after expansion. Furthermore, resting these expanded T cells in IL-2, IL-7 or IL-15 did not restore the antigen dependent responses. In contrast, T cells that were initially expanded with IL-2 + IL-7 rather than plate bound anti-CD3 + anti-CD28 retained responsiveness to antigen stimulation and these responses strongly correlated with responses measured at initial thawing.
Significance
While screening techniques for potential pathological autoantibodies have come a long way, comparable full-length protein target assays for screening patient T cells at medium throughput are noticeably lacking due to technical hurdles. Here we advance techniques that should have broad applicability to translational studies investigating cell mediated immunity in infectious or autoimmune diseases. Future studies are aimed at investigating possible CD8⁺ T cell autoantigens in MS and other CNS autoimmune diseases.
... Self-reactive T cells reaching the periphery are subject to constant control and suppression by Tregs [15,16]. Tregs are defined by the expression of the core transcription factor FoxP3 [17][18][19], high levels of CD25 (the α-chain of the IL-2 receptor, and low levels of the IL-7 receptor (CD127) [20] (CD4 + CD25 high CD127 low ) (for reviews, see [21][22][23]). ...
Immune-mediated cholangiopathies are characterised by the destruction of small and large bile ducts causing bile acid stasis, which leads to subsequent inflammation, fibrosis, and eventual cirrhosis of the liver tissue. A breakdown of peripheral hepatic immune tolerance is a key feature of these diseases. Regulatory T cells (Tregs) are a major anti-inflammatory immune cell subset, and their quantities and functional capacity are impaired in autoimmune liver diseases. Tregs can undergo phenotypic reprogramming towards pro-inflammatory Th1 and Th17 profiles. The inflamed hepatic microenvironment influences and can impede normal Treg suppressive functions. Mast cell (MC) infiltration increases during liver inflammation, and active MCs have been shown to be an important source of pro-inflammatory mediators, thus driving pathogenesis. By influencing the microenvironment, MCs can indirectly manipulate Treg functions and inhibit their suppressive and proliferative activity. In addition, direct cell-to-cell interactions have been identified between MCs and Tregs. It is critical to consider the effects of MCs on the inflammatory milieu of the liver and their influence on Treg functions. This review will focus on the roles and crosstalk of Tregs and MCs during autoimmune cholangiopathy pathogenesis progression.
... Some preclinical and clinical studies have shown Tregs are involved in autoimmune diseases [3], preventing graft vs. host disease (GvHD) [4], and graft rejection [5]. The discovery of Tregs has opened a new insight into their role in solid organ transplant rejection and mechanisms of tolerance in human diseases [6,7]. ...
The liver is considered a tolerogenic organ that can induce peripheral tolerance. The exact mechanisms of tolerance in the liver remain undefined. Regulatory T cells (Tregs) have been demonstrated to be involved in inducing and maintaining peripheral tolerance. They play an important role in the prevention of immune responses and autoimmunity.
The main focus of this review is the role of Tregs and their subpopulation in liver transplantation. More specifically, this manuscript will highlight the recent findings about using Treg cells as a biomarker in liver transplantation. There are some reports and animal models about the role of Tregs in the process of rejection of liver transplantation. Previous reports and studies have suggested that by increasing the number of Tregs better liver transplant outcomes will be accomplished by enhancing tolerance. It has been shown that the levels of CD4 + CD25 + FOXP3+ Treg cells correlate with the inhibition of acute allograft rejection in liver transplantation; however, further studies must be done to address the potential role of Treg cells in chronic rejection. Indeed, in the future, Treg cells may have potential use as a beneficial biomarker to screen long-term graft function.
... Tregs are very important in maintaining tolerance. Treg's ability to preserve their tolerance means that are vital to controlling and preventing autoimmune diseases [10]. Irregularities in the number Treg and function can result in loss of tolerance and autoimmune disease. ...
Regulatory T cells (Tregs) have the role of regulating self-tolerance, and suppressing immune responses. Defects in Treg function and number can lead to in loss of tolerance or autoimmune disease. To treat or control autoimmune diseases, one of the options is to develop immune tolerance for Tregs cell therapy, which includes promotion and activation. Recently, cell-based treatment as a promising approach to increase cells function and number has been developed. Cell therapy by chimeric T antigen receptor (CAR-T) cells has shown significant efficacy in the treatment of leukemia, which has led researchers to use CAR-T cells in other diseases like autoimmune diseases. Here, we describe the existing treatments for autoimmune diseases and the available treatments based on Treg, their benefits and restrictions for implementation in clinical trials. We also discussed potential solutions to overcome these limitations. It seems novel designs of CARs to be new hope for autoimmune diseases and expected to be a potential cure option in a wide array of disease in the future. Therefore, it is very important to address this issue and increase information about it.
