-
Kardiochirurgia I Torakochirurgia... Dec 2023Mediastinal tumors encompass a diverse range of malignancies, originating within or spreading to the mediastinum. The administration of radiotherapy within the... (Review)
Review
Mediastinal tumors encompass a diverse range of malignancies, originating within or spreading to the mediastinum. The administration of radiotherapy within the anatomical confines of the mediastinum presents unique challenges owing to the close proximity of critical organs, including the heart, lungs, esophagus, and spinal cord. However, recent progress in imaging techniques, treatment modalities, and our understanding of tumor biology has significantly contributed to the development of effective and safe therapeutic strategies for mediastinal diseases. This review article aims to explore the latest innovations in radiotherapy and their practical applications in the management of mediastinal tumors, with a primary focus on lymphomas, thymomas, and thymic carcinomas. By examining these advancements, we seek to provide valuable insights into the current state of the art in radiotherapy for mediastinal malignancies, ultimately fostering improved patient outcomes and clinical decision-making.
PubMed: 38283558
DOI: 10.5114/kitp.2023.134132 -
Frontiers in Immunology 2023T cells have an essential role in adaptive immunity against pathogens and cancer, but failure of thymic tolerance mechanisms can instead lead to escape of T cells with... (Review)
Review
T cells have an essential role in adaptive immunity against pathogens and cancer, but failure of thymic tolerance mechanisms can instead lead to escape of T cells with the ability to attack host tissues. Multiple sclerosis (MS) occurs when structures such as myelin and neurons in the central nervous system (CNS) are the target of autoreactive immune responses, resulting in lesions in the brain and spinal cord which cause varied and episodic neurological deficits. A role for autoreactive T cell and antibody responses in MS is likely, and mounting evidence implicates Epstein-Barr virus (EBV) in disease mechanisms. In this review we discuss antigen specificity of T cells involved in development and progression of MS. We examine the current evidence that these T cells can target multiple antigens such as those from pathogens including EBV and briefly describe other mechanisms through which viruses could affect disease. Unravelling the complexity of the autoantigen T cell repertoire is essential for understanding key events in the development and progression of MS, with wider implications for development of future therapies.
Topics: Humans; Herpesvirus 4, Human; Multiple Sclerosis; Epstein-Barr Virus Infections; Brain; Central Nervous System
PubMed: 38022632
DOI: 10.3389/fimmu.2023.1304281 -
Lab Animal Jul 2023Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including... (Review)
Review
Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone marrow, liver, thymus humanized mouse, which uses fetal tissues for generating a chimeric human immune system, the NeoThy humanized mouse uses nonfetal tissue sources. Specifically, the NeoThy model incorporates hematopoietic stem and progenitor cells from umbilical cord blood (UCB) as well as thymus tissue that is typically discarded as medical waste during neonatal cardiac surgeries. Compared with fetal thymus tissue, the abundant quantity of neonatal thymus tissue offers the opportunity to prepare over 1,000 NeoThy mice from an individual thymus donor. Here we describe a protocol for processing of the neonatal tissues (thymus and UCB) and hematopoietic stem and progenitor cell separation, human leukocyte antigen typing and matching of allogenic thymus and UCB tissues, creation of NeoThy mice, assessment of human immune cell reconstitution and all experimental steps from planning and design to data analysis. This entire protocol takes a total of ~19 h to complete, with steps broken up into multiple sessions of 4 h or less that can be paused and completed over multiple days. The protocol can be completed, after practice, by individuals with intermediate laboratory and animal handling skills, enabling researchers to make effective use of this promising in vivo model of human immune function.
Topics: Humans; Animals; Mice; Immune System; Thymus Gland; Disease Models, Animal; Liver; Research Personnel
PubMed: 37386161
DOI: 10.1038/s41684-023-01196-z -
Frontiers in Immunology 2023Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and...
Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and inducible γδT17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from immature γδT17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward Vγ4. Although IL-23 is known to be involved in developing γδT17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of γδT17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of nγδT17 cells but is required for the peripheral maintenance of Vγ4nγδT17 cells. Upon stimulation with γδTCR, IL-1 plus IL-21 induces the proliferation of Vγ4nγδT17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature γδT17 cells are produced in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced Vγ4γδT17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of γδT17 cells, we found that IL-21 receptors on γδT17 cells are involved in maintaining Vγ4γδT17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of Vγ4γδT17 cells.
Topics: Animals; Mice; Interleukin-1; Interleukin-17; Interleukin-23; Interleukins; T-Lymphocyte Subsets
PubMed: 37662923
DOI: 10.3389/fimmu.2023.1211620 -
Journal of Neuroinflammation Sep 2023Spinal cord injury (SCI), which causes loss of sensory and motor function in the body below the level of injury, is a devastating disease of the central nervous system....
BACKGROUND
Spinal cord injury (SCI), which causes loss of sensory and motor function in the body below the level of injury, is a devastating disease of the central nervous system. SCI leads to severe secondary immunosuppression, called SCI-induced immunodeficiency syndrome (SCI-IDS), which is characterized by increased susceptibility to infection and further exacerbates neurological dysfunction. Several studies have suggested that SCI-IDS is an independent risk factor for poor neurological prognosis. SCI-IDS predominantly occurs following injury above the T5 levels and eventually leads to systemic immune failure, possibly via the sympathetic-adrenal medullary axis and the hypothalamic‒pituitary‒adrenal (HPA) axis. However, the mechanism remains unclear.
METHODS AND OBJECTIVES
The concentrations of adrenocorticotropic hormone and cortisol in plasma, as well as changes in sympathetic activity (blood pressure and catecholamine levels in plasma), were assessed in rats in the high-level (T3) spinal cord injury (T3-SCI) group and the low-level (T10) spinal cord injury (T10-SCI) group. Second, the differential regulation of the gene network between the sympathetic-adrenal medullary axis and the HPA axis was explored by histology and multitissue transcriptomics, and the neuroendocrine-immune network associated with SCI-IDS was further elucidated.
RESULTS
The spleen and thymus gland, which are secondary immune organs, were significantly atrophied in rats in the T3-SCI group, and the white pulp of the spleen was significantly atrophied. The level of cortisol, which is mediated by the adrenal glands, was markedly elevated, but norepinephrine levels were markedly decreased. There was no difference in adrenocorticotropic hormone expression between any of the groups. The transcriptome analysis results showed that the downregulated differentially expressed genes (DEGs) in the T3-SCI group were enriched in the GO term immunoregulation, indicating that splenic immune function was markedly impaired after high-level SCI. The upregulated DEGs in the hypothalamus (hub genes: Nod2, Serpine1, Cebpb, Nfkbil1, Ripk2, Zfp36, Traf6, Akap8, Gfer, Cxcl10, Tnfaip3, Icam1, Fcgr2b, Ager, Dusp10, and Mapkapk2) were significantly enriched in inflammatory pathways, and the downregulated genes (hub genes: Grm4, Nmu, P2ry12, rt1-bb1, Oprm1, Zfhx2, Gpr83, and Chrm2) were enriched in pathways related to inhibitory Gi-mediated G protein-coupled receptor (Gi-GPCR) neurons and neuropeptide changes. The upregulated genes in the adrenal glands (hub genes: Ciart, per2, per3, cry1, and cry2) were enriched in cortisol secretion and circadian rhythm changes, and the downregulated genes (hub genes: IL7r, rt1-bb, rt1-bb1, rt1-da, rt1-ba, cd74, cxcr3, vcam1, ccl5, bin1, and IL8) were significantly enriched in MHC-mediated immune responses.
CONCLUSIONS
To explore the possible mechanism underlying SCI-IDS, this study assessed the differential regulation of the gene network associated with neuroendocrine immunity after SCI. Progressive neuroinflammation spreads after injury, and neurotransmission through Gi-mediated G protein-coupled receptors in the HPA axis and neuropeptide production by the hypothalamus are inhibited. Disruption of the connection between the hypothalamus and the adrenal glands causes autonomous regulation of the adrenal glands, disturbance of circadian rhythm and finally hypercortisolemia, leading to general suppression of peripheral adaptive immunity. Neuraxial nerve inflammation caused by SCI persists indefinitely, blocking nerve repair; persistent system-wide immunosuppression in the periphery results in increased susceptibility to infection, leading to poor neurological prognosis.
Topics: Rats; Animals; Hypothalamo-Hypophyseal System; Hydrocortisone; Transcriptome; Pituitary-Adrenal System; Spinal Cord Injuries; Gene Expression Profiling; Adrenocorticotropic Hormone
PubMed: 37775760
DOI: 10.1186/s12974-023-02906-7 -
Journal of Traditional Chinese Medicine... Oct 2023To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor...
Zhenxin Anshen formula ameliorates atopic der-matitis-like skin dysfunction in mice and regulation of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 in Neural pathways.
OBJECTIVE
To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) signalling pathway in mice and .
METHODS
AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. BALB/c mice were divided into five groups: normal control, model control, cetirizine, low-, medium-, and high-dose of ZXAS. After ZXAS in-tervention, the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines. Immun-oglobulin E (IgE), interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP) were de-tected by Enzyme-linked immunosorbent assay (ELISA). The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor (GRPR), TRPV1, and TRPA1 by using immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. In addition, 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, ELISA, and Western blotting were conducted for analysis of primary dorsal root ganglia (DRG) neurons .
RESULTS
ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score, number of scratching and epidermal thickness, accompanied by the de-creased IgE and Th2 inflammatory cytokines. ZXAS also supressed the mRNA and protein expression of GRPR, TRPV1, and TRPA1 in the spinal cord. The medicated sera of ZXAS decreased capsaicin-induced Ca influx and downregulated the expression of TRPV1, TRPA1, and phospholipase C in DRG neurons.
CONCLUSIONS
The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca2+ signals in neurons.
Topics: Animals; Mice; Ankyrins; Dinitrochlorobenzene; Antineoplastic Agents; Dermatitis, Atopic; Cytokines; Neural Pathways; Dinitrobenzenes; Immunoglobulin E
PubMed: 37679976
DOI: 10.19852/j.cnki.jtcm.20230802.003 -
Evidence-based Complementary and... 2023Angelica Yinzi (AYZ) is a Chinese traditional herbal formula reported to attenuate itches and inflammation caused by atopic dermatitis (AD). However, the underlying...
BACKGROUND
Angelica Yinzi (AYZ) is a Chinese traditional herbal formula reported to attenuate itches and inflammation caused by atopic dermatitis (AD). However, the underlying mechanism of AYZ in the attenuation of itchiness and inflammation remains unknown.
OBJECTIVE
This study investigated the mechanism of AYZ in reducing itchiness in mice with 1-chloro-2,4-dinitrobenzene- (DNCB-)-induced atopic dermatitis.
METHODS
Hematoxylin and eosin (H&E) and toluidine blue staining were used to evaluate pathological changes in skin tissue, while an enzyme-linked immunosorbent assay (ELISA) was used to assess the cytokine levels in the skin. After that, qRT-PCR was performed to determine the mRNA levels of cytokines in the skin. Immunofluorescence and western blotting analysis were further used to assess -opioid receptor (MOR) expression and immunohistochemistry to assess the p-ERK, p-AKT, and -opioid receptor (KOR).
RESULTS
The AYZ treatment alleviated the AD clinical symptoms, including decreasing the scratching frequency, the ear thickness, and the infiltration of mast cells, lymphocytes, inflammatory cells, and mononuclear cells. In addition, AYZ inhibited the expression of interleukin (IL)-13, thymic stromal lymphopoietin (TSLP), and reduced neuraminidase (NA), corticotropin-releasing factor (CRF), and reactive oxygen species (ROS) expression. Markers involved in itches, such as p-ERK and p-AKT, were significantly downregulated following AYZ treatment. Besides, AYZ significantly increased MOR expression and downregulated KOR in the epidermis and spinal cord.
CONCLUSION
Our findings imply that AYZ ameliorates pruritus-related AD through skin repair, antioxidation, and balancing peripheral MOR and KOR. The findings in this study lay a theoretical foundation for the control mechanism of peripheral itch.
PubMed: 37790739
DOI: 10.1155/2023/6058951 -
Aging Apr 2024Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord...
BACKGROUND
Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) reverse the structure and function of the senescent thymus . However, the transcriptomic regulation mechanism is unclear.
METHODS
TECs were cultured with HO for 72 hours to induce senescence. UCMSCs were cocultured with senescent TECs for 48 hours to detect SA-β-gal, P16 and Ki67. The cocultured TECs were collected for lncRNA, mRNA and miRNA sequencing to establish a competitive endogenous regulatory network (ceRNA). And RT-qPCR, immunofluorescence staining, and western blot were used to identified key genes.
RESULTS
Our results showed that HO induced TEC aging and that UCMSCs reversed these changes. Compared with those in aged TECs, 2260 DE mRNAs, 1033 DE lncRNAs and 67 DE miRNAs were differentially expressed, and these changes were reversed by coculturing the cells with UCMSCs. Differential mRNA enrichment analysis of ceRNA regulation revealed that the PI3K-AKT pathway was a significant signaling pathway. UCMSC coculture upregulated VEGFA, which is the upstream factor of the PI3K-AKT signaling pathway, and the expression of the key proteins PI3K and AKT. Thus, the expression of the cell cycle suppressor P27, which is downstream of the PI3K-AKT signaling pathway, was downregulated, while the expression of the cell cycle regulators CDK2 and CCNE was upregulated.
CONCLUSION
UCMSC coculture upregulated the expression of VEGFA, activated the PI3K-AKT signaling pathway, increased the expression of CDK2 and CCNE, decreased the expression of P27, and promoted the proliferation of TECs.
Topics: Mesenchymal Stem Cells; Humans; Epithelial Cells; Cellular Senescence; Umbilical Cord; Gene Expression Profiling; Thymus Gland; Coculture Techniques; MicroRNAs; Cyclin-Dependent Kinase 2; Cyclin E; Biomarkers; Hydrogen Peroxide; Signal Transduction; Vascular Endothelial Growth Factor A; Phosphatidylinositol 3-Kinases; Cells, Cultured; Proto-Oncogene Proteins c-akt; RNA, Long Noncoding; Transcriptome; Cyclin-Dependent Kinase Inhibitor p27; Oncogene Proteins
PubMed: 38637117
DOI: 10.18632/aging.205738 -
Frontiers in Immunology 2023Previously, we achieved large-scale expansion of bone marrow-derived suppressor cells (MDSCs) derived from cluster of differentiation (CD)34 cells cultured in human...
INTRODUCTION
Previously, we achieved large-scale expansion of bone marrow-derived suppressor cells (MDSCs) derived from cluster of differentiation (CD)34 cells cultured in human umbilical cord blood (hUCB) and demonstrated their immunomodulatory properties. In the present study, we assessed the therapeutic efficacy of hUCB-MDSCs in atopic dermatitis (AD).
METHODS
(Df)-induced NC/Nga mice (clinical score of 7) were treated with hUCB-MDSCs or a control drug. The mechanisms underlying the therapeutic effects of hUCB-MDSCs were evaluated.
RESULTS AND DISCUSSION
hUCB-MDSCs demonstrated immunosuppressive effects in both human and mouse CD4 T cells. hUCB-MDSCs significantly reduced the clinical severity scores, which were associated with histopathological changes, and reduced inflammatory cell infiltration, epidermal hyperplasia, and fibrosis. Furthermore, hUCB-MDSCs decreased the serum levels of immunoglobulin E, interleukin (IL)-4, IL-5, IL-13, IL-17, thymus- and activation-regulated chemokines, and thymic stromal lymphopoietin. Additionally, they altered the expression of the skin barrier function-related proteins filaggrin, involucrin, loricrin, cytokeratin 10, and cytokeratin 14 and suppressed the activation of Df-restimulated T-cells via cell-cell interactions. hUCB-MDSCs promoted skin recovery and maintained their therapeutic effect even after recurrence. Consequently, hUCB-MDSC administration improved Df-induced AD-like skin lesions and restored skin barrier function. Our findings support the potential of hUCB-MDSCs as a novel treatment strategy for AD.
Topics: Humans; Animals; Mice; Dermatitis, Atopic; Fetal Blood; Myeloid Cells; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes
PubMed: 38264643
DOI: 10.3389/fimmu.2023.1263646 -
International Journal of Molecular... Jul 2023Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via...
Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via the intra-bone marrow injection of CD133+ cord blood cells into irradiated adult immunodeficient mice (IBMI-huNSG mice), which could mount functional immune responses against HTLV-1, although the underlying mechanisms were still unknown. Here, we investigated thymocyte development in IBMI-huNSG mice, focusing on the roles of human and mouse MHC restriction. IBMI-huNSG mice had normal developmental profiles but aberrant thymic structures. Surprisingly, the thymic medulla-like regions expanded after immunization due to enhanced thymocyte expansion in association with the increase in HLA-DR+ cells, including CD205 dendritic cells (DCs). The organ culture of thymus from immunized IBMI-huNSG mice with a neutralizing antibody to HLA-DR showed the HLA-DR-dependent expansion of CD4 single positive thymocytes. Mature peripheral T-cells exhibited alloreactive proliferation when co-cultured with human peripheral blood mononuclear cells. Live imaging of the thymus from immunized IBMI-huNSG mice revealed dynamic adhesive contacts of human-derived thymocytes and DCs accompanied by Rap1 activation. These findings demonstrate that an increase in HLA-DR+ cells by immunization promotes HLA-restricted thymocyte expansion in humanized mice, offering a unique opportunity to generate humanized mice with ease.
Topics: Humans; Mice; Animals; Thymocytes; Leukocytes, Mononuclear; Antigen-Presenting Cells; Thymus Gland; HLA-DR Antigens; Immunization
PubMed: 37511462
DOI: 10.3390/ijms241411705