22 results match your criteria suppression thymopoiesis

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A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations.

J Dermatol Sci 2019 Mar 8;93(3):176-185. Epub 2019 Mar 8.

Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan.

Background: Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas.

Objective: We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. Read More

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Inhibition of thymocyte autophagy-associated CD4T thymopoiesis is involved in asthma susceptibility in mice exposed to caffeine prenatally.

Arch Toxicol 2019 05 25;93(5):1323-1335. Epub 2019 Feb 25.

Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, 185, East Lake Road, Wuhan, 430071, China.

Our previous studies demonstrated that prenatal caffeine exposure (PCE) caused thymopoiesis inhibition, immune disorders, and airway remodeling in offspring, which raises the question of whether PCE is a risk factor for postnatal asthma. Meanwhile, the mechanism of PCE-induced thymopoiesis inhibition is not clear yet. Considering caffeine's pro-autophagy effects (lacking evidence in thymus) and the important role of autophagy in maintaining thymopoiesis, this study aimed to investigate whether PCE contributes to asthma susceptibility, and further explore the molecular mechanisms of thymopoiesis inhibition from the perspective of pro-autophagy effects of caffeine both in vivo and in vitro. Read More

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Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System.

Cell Rep 2018 03;22(12):3175-3190

Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4CD8 double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8αβ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). Read More

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Sublethal Total Body Irradiation Causes Long-Term Deficits in Thymus Function by Reducing Lymphoid Progenitors.

J Immunol 2017 10 20;199(8):2701-2712. Epub 2017 Sep 20.

Department of Genetics, Paul D. Coverdell Center, University of Georgia, Athens, GA 30602;

Total body irradiation (TBI) damages hematopoietic cells in the bone marrow and thymus; however, the long-term effects of irradiation with aging remain unclear. In this study, we found that the impact of radiation on thymopoiesis in mice varied by sex and dose but, overall, thymopoiesis remained suppressed for ≥12 mo after a single exposure. Male and female mice showed a long-term dose-dependent reduction in thymic cKit lymphoid progenitors that was maintained throughout life. Read More

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October 2017

Decreases in thymopoiesis of astronauts returning from space flight.

JCI Insight 2016 08 4;1(12):e88787. Epub 2016 Aug 4.

Adult Stem Cell Transplant Program, University of Miami Sylvester Cancer Center, Miami, Florida, USA.

Following the advent of molecular assays that measure T cell receptor excision circles (TRECs) present in recent thymic emigrants, it has been conclusively shown that thymopoiesis persists in most adults, but that functional output decreases with age, influencing the maintenance of a diverse and functional T cell receptor (TCR) repertoire. Space flight has been shown to result in a variety of phenotypic and functional changes in human T cells and in the reactivation of latent viruses. While space flight has been shown to influence thymic architecture in rodents, thymopoiesis has not previously been assessed in astronauts. Read More

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Antagonist effect of Interleukin 1 receptor on normal thymopoiesis and thymus toxicity of 5-azacytidine in mouse.

Am J Transl Res 2016 15;8(2):1237-45. Epub 2016 Feb 15.

Laboratory of Regeneration, School of Pharmacy, Shanghai Jiao Tong University Shanghai 200240, China.

Thymopoiesis is essential and significant for development and maintenance of the robust and healthy immune system. The acute suppression of thymopoiesis induced by 5-Azacytidine (5-Aza) is an intractable clinical problem complicating chemotherapy. Interleukin 1 receptor antagonist (IL-1Ra) is a cytokine that competitively blocks binding of interleukin 1 (IL-1) to its receptor. Read More

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Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.

Immun Ageing 2015 29;12:18. Epub 2015 Oct 29.

Department of Human Genetics, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary ; Biosystems International Kft, Debrecen, Hungary.

Background: Thymic involution is thought to be an important factor of age related immunodeficiency. Understanding the molecular mechanisms of human thymic senescence may lead to the discovery of novel therapeutic approaches aimed at the reestablishment of central and peripheral T cell repertoire.

Results: As an initial approach, here we report that the decline of human thymic FOXN1 transcription correlates with age, while other genes, DLL1, DLL4 and WNT4, essential for thymopoiesis, are constitutively transcribed. Read More

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October 2015

Immune cell reconstitution after exposure to potentially lethal doses of radiation in the nonhuman primate.

Health Phys 2014 Jan;106(1):84-96

*University of Maryland, School of Medicine, Dept. of Radiation Oncology, Baltimore, MD; †Integrated Research Facility, Frederick, MD; ‡Naval Medical Research Center, Silver Spring, MD.

Delayed immune reconstitution remains a major cause of morbidity associated with myelosuppression induced by cytotoxic therapy or myeloablative conditioning for stem cell transplant, as well as potentially lethal doses of total- or partial-body irradiation. Restoration of a functional immune cell repertoire requires hematopoietic stem cell reconstitution for all immune cells and effective thymopoiesis for T cell recovery. There are no medical countermeasures available to mitigate damage consequent to high-dose, potentially lethal irradiation, and there are no well characterized large animal models of prolonged immunosuppression to assess efficacy of potential countermeasures. Read More

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January 2014

Downregulation of BCL11A by siRNA induces apoptosis in B lymphoma cell lines.

Biomed Rep 2013 Jan 5;1(1):47-52. Epub 2012 Sep 5.

Institute of Hematology, Medical College; ; Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong 510632, P.R. China.

The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11A gene (BCL11A) encodes a krüppel-like zinc finger protein, which is important in thymopoiesis and has been associated with hematopoietic malignancies. In this study, we investigated whether the downregulation of BCL11A mRNA by small interference RNA (siRNA) was capable of inducing apoptosis, and tested the effect of BCL11A siRNA combined with BCL2 siRNA in B lymphoma cell lines (SUDHL6, EB1). BCL11A siRNA was transfected into SUDHL6, EB1 cells with HiPerfect transfection reagents. Read More

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January 2013

Runx3 is a crucial regulator of alveolar differentiation and lung tumorigenesis in mice.

Differentiation 2011 Apr 1;81(4):261-8. Epub 2011 Mar 1.

Division in Anatomy and Developmental Biology, Department of Oral Biology, Research Center for Orofacial Hard Tissue Regeneration, Brain Korea 21 project, Oral Science Research Center, College of Dentistry, Yonsei Center of Biotechnology, Yonsei University, Seoul, Republic of Korea.

The runt-domain transcription factor Runx3 plays crucial roles during development such as regulating gene expression. It has been shown that Runx3 is involved in neurogenesis, thymopoiesis and functions like a tumor suppressor. Runx3 null mouse die soon after birth as a result of multiple organ defects. Read More

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Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice.

Oncogene 2010 May 15;29(19):2877-83. Epub 2010 Feb 15.

Department of Immunology, IMIM-Hospital del Mar, Barcelona Biomedical Research Park, Barcelona, Spain.

Poly(ADP-ribose) polymerase-2 (Parp-2) belongs to a family of enzymes that catalyse poly(ADP-ribosyl)ation of proteins. Parp-2 deficiency in mice (Parp-2(-/-)) results in reduced thymic cellularity associated with increased apoptosis in thymocytes, defining Parp-2 as an important mediator of T-cell survival during thymopoiesis. To determine whether there is a link between Parp-2 and the p53 DNA-damage-dependent apoptotic response, we have generated Parp-2/p53-double-null mutant mice. Read More

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Thymic involution: implications for self-tolerance.

Methods Mol Biol 2007 ;380:377-90

Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD, USA.

The thymus contributes to the regulation of tolerance and the prevention of autoimmunity at many levels. First, auto-reactive CD4+ and CD8+ T cells are clonally deleted during negative selection in the thymus, establishing central tolerance. The unique expression of the AIRE (autoimmune regulator) gene in medullary thymic epithelial cells results in expression of a broad array of tissue-specific antigens. Read More

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Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells.

Oncogene 2007 May 18;26(26):3797-810. Epub 2006 Dec 18.

Clinic for Internal Medicine C, University of Greifswald, Greifswald, Germany.

The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Krüppel-like zinc-finger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumor-suppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Read More

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Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection.

Blood 2007 Apr;109(7):2912-20

Laboratoire d'Immunologie, Centre de Recherches du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Hôpital Saint Luc, Montreal, QC, Canada.

In chronic HIV infection, most untreated patients lose naive CD4+ and CD8+ T cells, whereas a minority preserve them despite persistent high viremia. Although antiretroviral therapy (ART)-mediated viral suppression generally results in a rise of naive and total CD4+ T cells, certain patients experience very little or no T-cell reconstitution. High peripheral T-cell activation has been linked to poor clinical outcomes, interfering with previous evaluations of thymic function in disease progression and therapy-mediated T-cell recovery. Read More

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Notch1 and IL-7 receptor interplay maintains proliferation of human thymic progenitors while suppressing non-T cell fates.

J Immunol 2006 Sep;177(6):3711-20

Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.

Notch signaling is critical for T cell development of multipotent hemopoietic progenitors. Yet, how Notch regulates T cell fate specification during early thymopoiesis remains unclear. In this study, we have identified an early subset of CD34high c-kit+ flt3+ IL-7Ralpha+ cells in the human postnatal thymus, which includes primitive progenitors with combined lymphomyeloid potential. Read More

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September 2006

TGF-beta signaling in T cells: roles in lymphoid and epithelial neoplasia.

Authors:
John J Letterio

Oncogene 2005 Aug;24(37):5701-12

The Laboratory of Cell Regulation and Carcinogenesis, The Center for Cancer Research, The National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA.

Transforming growth factor-beta (TGF-beta) plays an essential role in regulating the homeostasis of cells in the lymphoid lineage. TGF-beta signaling is not required for normal thymopoiesis, but is essential for regulating the expansion, activation, and effector function of the mature CD4+ and CD8+ T cells in the peripheral lymphoid organs and target tissues. Recent studies in both mice and humans have elucidated an important and complex role for TGF-beta in regulatory T-cell biology. Read More

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Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome.

Blood 2004 Oct 20;104(8):2574-81. Epub 2004 Apr 20.

Department of Pediatrics, Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.

Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppression followed by postnatal thymus transplantation would lead to T-cell function in 6 infant patients who had host T cells at the time of transplantation. Read More

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October 2004

RNA-based anti-HIV-1 gene therapeutic constructs in SCID-hu mouse model.

Mol Ther 2002 Dec;6(6):770-82

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.

Effective suppression of HIV-1 replication requires inhibition of critical viral target molecules. Tat and Rev are indispensable regulatory factors for HIV-1 replication, whereas Env mediates virus entry by direct interaction with surface receptor CD4 and coreceptor CCR5 or CXCR4. Anti-HIV-1 tat-rev and env ribozymes and Rev aptamers were previously demonstrated to provide relatively long-term protection against HIV-1 infection in vitro. Read More

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December 2002

Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification.

J Immunol 2002 Apr;168(7):3173-80

Arthur and Sonia Labatt Brain Tumor Research Center and Program in Developmental Biology, Hospital for Sick Children, Toronto, Ontario, Canada.

The conserved adaptor protein Numb is an intrinsic cell fate determinant that functions by antagonizing Notch-mediated signal transduction. The Notch family of membrane receptors controls cell survival and cell fate determination in a variety of organ systems and species. Recent studies have identified a role for mammalian Notch-1 signals at multiple stages of T lymphocyte development. Read More

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T cell receptor excision circle (TREC) content following maximum HIV suppression is equivalent in HIV-infected and HIV-uninfected individuals.

AIDS 2001 Sep;15(14):1757-64

Department of Immunology/Microbiology, Rush-Presbyterian-St Luke's Medical Center, Chicago, Illinois 60612, USA.

Background: The adult human thymus contributes to de novo T cell synthesis; such synthesis can be assessed by analyzing T cell receptor excision circles (TREC).

Methods: TREC levels were measured in total peripheral blood mononuclear cells (PBMC) and CD4- and CD8-enriched cells of 29 HIV-positive patients with maximal viral suppression. The expression of CD45RA+CD45RO-, CD45RA+CD62L+, CD45RO-CD27+CD95low and HLA-DR+CD38+ was assessed using three-color flow cytometric analysis of whole blood. Read More

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September 2001

Analysis of telomere length and thymic output in fast and slow/non-progressors with HIV infection.

Biomed Pharmacother 2000 Feb;54(1):21-31

Center for NeuroVirology and Cancer Biology, Temple University, Philadelphia, PA 19122, USA.

There are two models for CD4+ T-cell depletion leading to AIDS: a kinetic model and an immune suppression model. In the kinetic model, direct cell killing due to viral replication results in a continuous demand for CD4+ T-cells, which eventually exhausts their capacity for renewal by proliferative mechanisms. In the immune suppression model, CD4+ T-cell decline is due to an indirect global inhibitory effect of the virus on uninfected immune cell function. Read More

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February 2000

Reconstitution of human thymic implants is limited by human immunodeficiency virus breakthrough during antiretroviral therapy.

J Virol 1999 Aug;73(8):6361-9

Division of Hematology/Oncology, Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095-1678, USA.

Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4(+) cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Read More

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