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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 2020T cell-mediated immune tolerance is a state of unresponsiveness of T cells towards specific self or non-self antigens. This is particularly essential during... (Review)
Review
T cell-mediated immune tolerance is a state of unresponsiveness of T cells towards specific self or non-self antigens. This is particularly essential during prenatal/neonatal period when T cells are exposed to dramatically changing environment and required to avoid rejection of maternal antigens, limit autoimmune responses, tolerate inert environmental and food antigens and antigens from non-harmful commensal microorganisms, promote maturation of mucosal barrier function, yet mount an appropriate response to pathogenic microorganisms. The cell-intrinsic and cell extrinsic mechanisms promote the generation of prenatal/neonatal T cells with distinct features to meet the complex and dynamic need of tolerance during this period. Reduced exposure or impaired tolerance in early life may have significant impact on allergic or autoimmune diseases in adult life. The uniqueness of conventional and regulatory T cells in human umbilical cord blood (UCB) may also provide certain advantages in UCB transplantation for hematological disorders.
Topics: Age Factors; Animals; Cord Blood Stem Cell Transplantation; Humans; Immune Tolerance; Infant; Infant, Newborn; Phenotype; Receptors, Antigen, T-Cell; Self Tolerance; T-Lymphocytes; Thymus Gland; Transplantation, Homologous; Umbilical Cord
PubMed: 33329542
DOI: 10.3389/fimmu.2020.576261 -
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 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 -
International Journal of Molecular... Jul 2017Itch is the main chief complaint in patients visiting dermatologic clinics and has the ability to deeply impair life quality. Itch results from activation of cutaneous... (Review)
Review
Itch is the main chief complaint in patients visiting dermatologic clinics and has the ability to deeply impair life quality. Itch results from activation of cutaneous nerve endings by noxious stimuli such as inflammatory mediators, neurotransmitters and neuropeptides, causing itch signal transduction from peripheral skin, through the spinal cord and thalamus, to the brain cortex. Primarily noninflammatory diseases, such as uremic pruritus, cause itch through certain pruritogens in the skin. In inflammatory skin diseases, atopic dermatitis (AD) is the prototypic disease causing intensive itch by aberrant skin inflammation and epidermal barrier disruption. Recent understanding of disease susceptibility, severity markers, and mechanisms have helped to develop targeted therapy for itch in AD, including monoclonal antibodies against IL-4, IL-13, thymic stromal lymphopoietin (TSLP), IgE and IL-31. Promising effects have been observed in some of them. In this review, we summarized targeted therapies for inflammatory itch in AD and for managing abnormal itch transductions in other common itching skin diseases.
Topics: Animals; Antibodies; Cytokines; Dermatitis, Atopic; Humans; Interleukin-13; Interleukin-4; Pruritus; Thymic Stromal Lymphopoietin
PubMed: 28698528
DOI: 10.3390/ijms18071485 -
Pediatric Allergy and Immunology :... Mar 2015The fetal immune system is a critical window of development. The epithelial cell-derived cytokines, thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33) have...
BACKGROUND
The fetal immune system is a critical window of development. The epithelial cell-derived cytokines, thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33) have received attention for their role in allergic responses but not been studied during this critical window. The objectives were to assess correlations among IL-33, TSLP, and IgE in umbilical cord blood samples and identify prenatal predictors of these biomarkers.
METHODS
This study utilized data and banked cord blood collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2001 pregnant women. Our analytic sample comprised the 1254 women with a singleton, term birth with a cord blood sample. Spearman correlation coefficients (SCC) and logistic regression models were used to examine associations between biomarkers and identify potential predictors of elevated biomarker levels.
RESULTS
Thymic stromal lymphopoietin and IL-33 were more strongly correlated with each other (SCC = 0.75, p < 0.0001) than with IgE (IL-33 SCC = 0.14, TSLP SCC = 0.21). Maternal allergy, heavy street traffic, and elevated birth weight were significantly associated with jointly elevated TSLP and IL-33 levels, whereas maternal age and female infant sex were inversely associated with elevated IgE.
CONCLUSIONS
In this population of Canadian women and infants, TSLP and IL-33 were detectable in cord blood, more strongly correlated with each other than with IgE, and associated with maternal characteristics indicative of inflammatory responses. This study motivates investigation into the value of cord blood IL-33 and TSLP levels as childhood allergy predictors and raises interesting questions regarding in utero coordinated regulation of these cytokines.
Topics: Adult; Birth Weight; Cytokines; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Humans; Hypersensitivity; Interleukin-33; Mothers; Pregnancy; Young Adult; Thymic Stromal Lymphopoietin
PubMed: 25620084
DOI: 10.1111/pai.12340 -
Hematology/oncology and Stem Cell... Jun 2021While umbilical cord blood is increasingly utilized as a stem cell source, immune complications associated with the procedure have been recognized. These complications... (Review)
Review
While umbilical cord blood is increasingly utilized as a stem cell source, immune complications associated with the procedure have been recognized. These complications result from significant immune system dysregulation and defective reconstitution following transplant causing an imbalance between T-cell subsets, aberrant B cells, and abnormal antibody production. This may occur up to 12 months after transplant coinciding with thymic regeneration in adults. The aim of our review is to describe the incidence, pathophysiology, clinical features, and prognosis of autoimmune cytopenias following umbilical cord blood transplant. Furthermore, we review the treatment strategies reported in the existing literature, describe the authors' experience with the complication, and highlight novel treatment options being studied. The knowledge of the occurrence and timing of autoimmune complications of umbilical cord blood transplantation is essential for detection and treatment of the disease. Emerging therapeutic options include interleukin-2 (IL-2), which is also being studied for the treatment of acute and chronic graft-versus-host disease. IL-2 has favorable effects on growth, differentiation, and function of regulatory T cells. Monoclonal antibody treatments, such as daratumumab, are also on the forefront and more experience with them will guide further treatment strategies.
Topics: Anemia; Animals; Antibodies, Monoclonal; Autoimmune Diseases; B-Lymphocytes; Cord Blood Stem Cell Transplantation; Humans; Interleukin-2; Neutropenia; Purpura, Thrombocytopenic, Idiopathic; T-Lymphocytes
PubMed: 32882204
DOI: 10.1016/j.hemonc.2020.07.009 -
BioRxiv : the Preprint Server For... Apr 2023Within the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a...
Within the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a holistic, spatially defined map of tissue niches guiding postnatal T cell development we employed the multidimensional imaging platform CO-detection by indEXing (CODEX), as well as CITE-seq and ATAC-seq. We generated age-matched 4-5-month-old postnatal thymus datasets for male and female donors, and identify significant sex differences in both T cell and thymus biology. We demonstrate a crucial role for JAG ligands in directing thymic-like dendritic cell development, reveal important functions of a novel population of ECM fibroblasts, and characterize the medullary niches surrounding Hassall's corpuscles. Together, these data represent a unique age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, and provide an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.
PubMed: 37090676
DOI: 10.1101/2023.04.13.536804 -
Environmental Health : a Global Access... Jun 2015The fetal time period is a critical window of immune system development and resulting heightened susceptibility to the adverse effects of environmental exposures....
BACKGROUND
The fetal time period is a critical window of immune system development and resulting heightened susceptibility to the adverse effects of environmental exposures. Epidemiologists and toxicologists have hypothesized that persistent organic pollutants, pesticides and metals have immunotoxic properties. Immunotoxic effects may manifest as an altered immune system profile at birth. Immunoglobulin E, thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33) may be implicated in the etiology of childhood allergy and are detectable at birth. The objective of this study was to examine the potential relationship between maternal concentrations of metals, persistent organic pollutants, and pesticides and elevated umbilical cord blood concentrations of IgE, TSLP, and IL-33 in a Canadian birth cohort.
METHODS
This study utilized data collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2,001 pregnant women. Of these women, 1258 had a singleton, term birth and cord blood sample. Logistic regression was used to determine associations between log-transformed continuous variables and immune system biomarkers.
RESULTS
Inverse relationships were observed between lead, DDE, PCB-118, and a summary index of organophosphorous metabolites and jointly elevated concentrations of IL-33 and TSLP. None of the environmental contaminants were associated with increased odds of a high cord blood immune system biomarker concentration.
CONCLUSIONS
In this primarily urban Canadian population of pregnant women and their newborns, maternal blood or urine concentrations of persistent organic pollutants, pesticides, and metals were not associated with immunotoxic effects that manifest as increased odds of elevated concentrations of IgE, TSLP or IL-33.
Topics: Adult; Biomarkers; Canada; Cohort Studies; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Female; Fetal Blood; Hazardous Substances; Humans; Immunologic Factors; Infant; Infant, Newborn; Maternal Exposure; Metals; Pregnancy; Young Adult
PubMed: 26084354
DOI: 10.1186/s12940-015-0046-3 -
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