scholarly journals Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self-Antigen and Those That Present Antigen

2017 ◽  
Vol 199 (12) ◽  
pp. 3959-3971 ◽  
Author(s):  
Yasuhiro Mouri ◽  
Yoshihiro Ueda ◽  
Tomoyoshi Yamano ◽  
Minoru Matsumoto ◽  
Koichi Tsuneyama ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Cell Types ◽  
Self Antigen

scholarly journals Imaging Tolerance Induction in the Classic Medawar Neonatal Mouse Model: Active Roles of Multiple F1-Donor Cell Types

2015 ◽  
Vol 15 (9) ◽  
pp. 2346-2363 ◽  
Author(s):  
R. A. Bascom ◽  
K. S. Tao ◽  
S. L. Tollenaar ◽  
L. J. West
Keyword(s):  
Mouse Model ◽  
Tolerance Induction ◽  
Donor Cell ◽  
Cell Types ◽  
Neonatal Mouse

Hepatic T Cell Tolerance Induction in An Inflammatory Environment

2017 ◽  
Vol 36 (2) ◽  
pp. 156-166 ◽  
Author(s):  
Janine Dywicki ◽  
Fatih Noyan ◽  
Ana Clara Misslitz ◽  
Martin Hapke ◽  
Melanie Galla ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
T Cell Tolerance ◽  
Tolerance Mechanism ◽  
Autoreactive T Cells ◽  
Adenoviral Infection ◽  
Precursor Frequency ◽  
Self Antigen ◽  
Very High ◽  
Potential Tolerance

For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Under these conditions, hepatocytes mimic the generation of altered-self neoantigens. To follow autoreactive T cells during AIH, we adoptively transferred HA-­specific Cl4-TCR and 6.5-TCR T cells into Ad-Cre infected ­Rosa26-HA mice. Alternatively, Rosa26-HA mice have been crossed with TCR transgenic mice that were infected with Ad-Cre to break hepatic tolerance and induce the expression of the HA antigen as a hepatic self-antigen. Surprisingly, neither adoptive transfer nor a very high precursor frequency of autoreactive T cells was able to break tolerance in the context of adenoviral infection. The low proliferation of the antigen experienced autoreactive T cells despite the presence of the autoantigen and inflammation points to anergy as a potential tolerance mechanism. This model underscores the crucial importance of genetic susceptibility to break tolerance against hepatic autoantigens.

scholarly journals CD90- (Thy-1-) High Selection Enhances Reprogramming Capacity of Murine Adipose-Derived Mesenchymal Stem Cells

2013 ◽  
Vol 35 ◽  
pp. 573-579 ◽  
Author(s):  
Koichi Kawamoto ◽  
Masamitsu Konno ◽  
Hiroaki Nagano ◽  
Shimpei Nishikawa ◽  
Yoshito Tomimaru ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Tolerance Induction ◽  
Cell Types ◽  
Effective Strategy ◽  
Cell Sorter ◽  
High Selection ◽  
Selection Of

Background. Mesenchymal stem cells (MSCs), including adipose tissue-derived mesenchymal stem cells (ADSC), are multipotent and can differentiate into various cell types possessing unique immunomodulatory features. Several clinical trials have demonstrated the safety and possible efficacy of MSCs in organ transplantation. Thus, stem cell therapy is promising for tolerance induction. In this study, we assessed the reprogramming capacity of murine ADSCs and found that CD90 (Thy-1), originally discovered as a thymocyte antigen, could be a useful marker for cell therapy.Method. Murine ADSCs were isolated from B6 mice, sorted using a FACSAria cell sorter by selection ofCD90HiorCD90Lo, and then transduced with four standard factors (4F; Oct4, Sox2, Klf4, and c-Myc).Results. Unsorted,CD90Hi-sorted, andCD90Lo-sorted murine ADSCs were reprogrammed using standard 4F transduction.CD90HiADSCs showed increased numbers of alkaline phosphatase-positive colonies compared withCD90LoADSCs. The relative reprogramming efficiencies of unsorted,CD90Hi-sorted, andCD90Lo-sorted ADSCs were 100%, 116.5%, and 74.7%, respectively.CD90Hicells were more responsive to reprogramming.Conclusion.CD90HiADSCs had greater reprogramming capacity thanCD90LoADSCs, suggesting that ADSCs have heterogeneous subpopulations. Thus,CD90Hiselection presents an effective strategy to isolate a highly suppressive subpopulation for stem cell-based tolerance induction therapy.

scholarly journals CD47 and thrombospondin-1 regulation of mitochondria, metabolism, and diabetes

2021 ◽  
Author(s):  
David D. Roberts ◽  
Jeffrey S. Isenberg
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Innate Immune ◽  
Cell Behavior ◽  
Metabolic Dysfunction ◽  
Endocrine Dysfunction ◽  
High Affinity ◽  
Thrombospondin 1 ◽  
Health And Disease ◽  
Self Antigen

Thrombospondin-1 (TSP1) is the prototypical member of a family of secreted proteins that modulate cell behavior by engaging with molecules in the extracellular matrix and with receptors on the cell surface. CD47 is widely displayed on many, if not all, cell types and is a high affinity TSP1 receptor. CD47 is a self-antigen that limits innate immune cell activities, a feature recently exploited to enhance cancer immunotherapy. Another major role for CD47 in health and disease is to mediate TSP1 signaling. TSP1 acting through CD47 contributes to mitochondrial, metabolic and endocrine dysfunction. Studies in animal models found that elevated TSP1 expression, acting in part through CD47, causes mitochondrial and metabolic dysfunction. Clinical studies established that abnormal TSP1 expression positively correlates with obesity, fatty liver disease and diabetes. The unabated increase in these conditions worldwide and the availability of CD47 targeting drugs justify a closer look into how TSP1 and CD47 disrupt metabolic balance and the potential for therapeutic intervention.

Cytoarchitecture of the Xenopus thymus following gamma-irradiation

Development ◽  
1987 ◽  
Vol 100 (1) ◽  
pp. 95-105
Author(s):  
JH Russ ◽  
JD Horton
Keyword(s):  
Gamma Irradiation ◽  
Tolerance Induction ◽  
Cell Types ◽  
Whole Body ◽  
Thymic Stromal Cells ◽  
Normal Architecture

This paper describes in vitro and in vivo attempts to deplete the 4- to 8-month-old Xenopus laevis (J strain) thymus of its lymphocyte compartment. Gamma irradiation (2-3000 rad) of the excised thymus, followed by two weeks in organ culture, is effective in removing lymphocytes, but causes drastic reduction in size and loss of normal architecture. In contrast, in vivo whole-body irradiation (3000 rad) and subsequent in situ residence for 8-14 days proves successful in providing a lymphocyte-depleted froglet thymus without loss of cortical and medullary zones. In vivo-irradiated thymuses are about half normal size, lack cortical lymphocytes, but still retain some medullary thymocytes; they show no signs of lymphocyte regeneration when subsequently organ cultured for 2 weeks. Light microscopy of 1 micron, plastic-embedded sections and electron microscopy reveal that a range of thymic stromal cell types are retained and that increased numbers of cysts, mucous and myoid cells are found in the thymus following whole-body irradiation. In vivo-irradiated thymuses are therefore suitable for implantation studies exploring the role of thymic stromal cells in tolerance induction of differentiating T lymphocytes.

MART-1 transcript is absent in PBMCs from Vitiligo patients

2009 ◽  
Vol 4 (4) ◽  
pp. 528-535
Author(s):  
Marpe Bam ◽  
Tamishraha Bagchi
Keyword(s):  
Mononuclear Cells ◽  
Tolerance Induction ◽  
Peripheral Circulation ◽  
Peripheral Tolerance ◽  
Healthy Individuals ◽  
Peripheral Blood Mononuclear ◽  
Melanoma Antigen ◽  
Tolerance Breakdown ◽  
Self Antigen ◽  
Tyrosinase Related Protein

AbstractMechanisms occurring in the thymus and periphery are responsible for the generation and maintenance of tolerance in the immune system. Various reports have shown that the existence of an antigen in the peripheral circulation results in tolerance induction towards that protein. These observations imply that the lack of a self antigen can lead to induction of autoimmunity. Previously we have reported that Tyrosinase related protein-2 (TRP-2) transcripts from peripheral blood mononuclear cells (PBMCs) are absent in vitiligo patients but present in healthy individuals. Here, we show that MART1 (Melanoma antigen recognized by T cells) transcripts are not detected in the PBMCs of vitiligo patients but is detected in healthy controls. Our result suggests that as MART1 is not expressed in the PBMCs, MART1 is also not available for induction and maintenance of peripheral tolerance in vitiligo patients. We therefore conclude that nonexpression of MART1 in PBMCs of vitiligo patients may be somehow responsible for the tolerance breakdown finally resulting in the induction of autoimmunity seen against these self antigens in vitiligo.

scholarly journals Induction of Antigen-Specific Tolerance in Autoimmune Diabetes with Nanoparticles Containing Hybrid Insulin Peptides

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 240
Author(s):  
James E. DiLisio ◽  
Kathryn Haskins
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Cell Types ◽  
Dual Function ◽  
Transfer Model ◽  
Transplant Patients ◽  
Initial Work ◽  
Specific Tolerance

Autoreactive T cells are thought to orchestrate the onset and progression of autoimmune diabetes. Key cognate antigens of these diabetogenic T cells include hybrid insulin peptides, formed by the fusion of insulin fragments to cleavage products of other β-cell granule proteins. Here we review initial work exploring tolerance induction to a hybrid insulin peptide using a biodegradable, nanoparticle delivery system in non-obese diabetic (NOD) mice. The immune phenotype(s) and possible mechanism(s) behind antigen-specific tolerance induction were dissected with a disease transfer model using transgenic autoreactive mouse T cells. Treatment of NOD mice with peptide-coupled nanoparticles appeared to have a dual function in preventing diabetes onset, inducing anergy in effector T cells and enhancing the activity of regulatory T cells. Importantly, the ratio of these two cell types in the pancreas was pushed toward tolerance. Antigen-specific tolerance induction to hybrid insulin peptides has the translational potential to preserve islet β-cells in new-onset or at-risk patients and prevent recurrent autoimmunity in transplant patients.

scholarly journals Clonal deletion of self-reactive T cells in irradiation bone marrow chimeras and neonatally tolerant mice. Evidence for intercellular transfer of Mlsa.

1989 ◽  
Vol 170 (2) ◽  
pp. 595-600 ◽  
Author(s):  
D E Speiser ◽  
R Schneider ◽  
H Hengartner ◽  
H R MacDonald ◽  
R M Zinkernagel
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Tolerance Induction ◽  
Cell Types ◽  
Spleen Cells ◽  
Clonal Deletion ◽  
Variable Regions ◽  
Bone Marrow Derived Cells ◽  
Bone Marrow Chimeras ◽  
Different Cell Types

Tolerance to Mlsa has been shown to be associated with clonal deletion of cells carrying TCR beta chain variable regions V beta 6 or V beta 8.1 in mice possessing I-E antigens. To evaluate the rules of tolerance induction to Mlsa we prepared irradiation bone marrow chimeras expressing Mlsa or Mlsb and I-E by different cell types. Deletion of V beta 6+, Mlsa-reactive T cells required the presence of Mlsa and I-E products either on bone marrow-derived cells or on irradiated recipient cells. Tolerance was induced when Mlsa and I-E were expressed by distinct cells of the chimera. Also neonatally tolerized mice exhibited depletion of V beta 6+ cells after injection of I-E- Mlsa spleen cells (DBA/1) into newborn I-E+ Mlsb mice (BALB/c x B10.G)F1. These results suggest that the product of the Mlsa locus is soluble and/or may be transferred from cell to cell and bound to I-E antigens. The chimera experiments also showed that tolerance to Mlsa is H-2 allele independent, i.e., is apparently unrestricted. Differentiation of chimeric (H-2d/Mlsa x H-2q/Mlsb)F1 stem cells in either an H-2d or an H-2q thymus revealed that tolerance assessed by absence of V beta 6+ T cells is not dependent on the thymically determined restriction specificity of T cells.

scholarly journals NK and Th17 cells in the thymus of myasthenia gravis patients

Acta Medica ◽  
2020 ◽  
Vol 51 (3) ◽  
pp. 9-17
Author(s):  
Can Ebru Bekircan-Kurt
Keyword(s):  
Myasthenia Gravis ◽  
Nk Cells ◽  
Th17 Cells ◽  
Nk Cell ◽  
Tolerance Induction ◽  
Autoimmune Disorder ◽  
Cell Types ◽  
Activation Markers ◽  
Immune Tolerance Induction ◽  
Central Organ

Objective: As a classical autoimmune disorder, anti-acetylcholine receptor (AChR) antibody positive myasthenia gravis (MG) has an unconventional pathophysiology that involves thymus, the central organ for immune tolerance induction. Both natural killer (NK) cells and type 17 helper T (Th17) cells possess capacity to influence autoimmune inflammation. This study aims to determine the presence of Th17 and NK cells in the thymus from MG patients. Methods: Thymectomy materials of MG patients and non-MG controls were assessed by CD56, CD16, CD2, CD3, NKG2D, NKp46 and IL-23R flow cytometry and IL-23R, IL-21R, and ROR-γ immunohistochemistry. Results: Even though NK cell infiltration was limited, the majority of these cells displayed activation markers NKG2D and NKp46. Expectedly, the amount of CD2+ lymphocytic cells were higher than CD3+ thymocytes in which a considerable percentage was carrying the receptor for IL-23 (IL-23R). In addition to IL-23R, IL-21R, and ROR-γ were also detected in MG thymus as a marker related to Th17 cells. These Th17-related markers were reduced in thymoma compared to that of detected in thymic hyperplasia or the MG thymus with normal histopathology. Conclusion: Both NK cells and Th17 cells are found in the MG thymus indicating a possible cross-regulation between these cell types that may influence the course of autoimmune reactions.

scholarly journals NK cells promote transplant tolerance by killing donor antigen-presenting cells

2006 ◽  
Vol 203 (8) ◽  
pp. 1851-1858 ◽  
Author(s):  
Guang Yu ◽  
Xuemin Xu ◽  
Minh Diem Vu ◽  
Elizabeth D. Kilpatrick ◽  
Xian Chang Li
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Tolerance Induction ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Target Cells ◽  
Skin Allograft ◽  
Transplant Tolerance ◽  
Skin Allografts ◽  
Antigen Presenting

Natural killer (NK) cells are programmed to kill target cells without prior antigen priming. Because of their potent cytolytic activities, NK cells are one of the key cell types involved in dismantling allografts. However, in certain transplant models, NK cells also express potent immunoregulatory properties that promote tolerance induction. The precise mechanism for such striking dichotomy remains unknown. In the present study, we showed in a skin transplant model that the skin allografts contain a subset of antigen-presenting cells (APCs) that can home to the recipient mice. We also showed that such graft-derived APCs are usually destroyed by the host NK cells. But in the absence of NK cells, donor APCs can survive and then migrate to the host lymphoid and extralymphoid sites where they directly stimulate the activation of alloreactive T cells. T cells activated in the absence of NK cells are more resistant to costimulatory blockade treatment, and under such conditions stable skin allograft survival is difficult to achieve. Our study identified a novel role for NK cells in regulating T cell priming in transplant models, and may have important clinical implications in tolerance induction.

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