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  • The American Association of Immunologists  (4)
  • Hu, Hao  (4)
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  • The American Association of Immunologists  (4)
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  • 1
    Online Resource
    Online Resource
    The cellular basis of the PD-1/PD-L1 regulatory pathway in diabetic autoimmunity in the NOD mouse
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 116.5-116.5
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 116.5-116.5
    Abstract: We report our studies on the effects of checkpoint blockade on the development of diabetic autoimmunity in the NOD mouse. One of the complications of checkpoint blockade therapy in cancer patients is the development of acute type 1 diabetes (T1D). We confirm that the PD-1/PD-L1 regulatory pathway is highly involved in T1D in the NOD mouse. In NOD autoimmunity there is an entry of CD4+ T cells specific to insulin peptides shortly after weaning followed by CD103+ dendritic cells (DC), CD4+ T cells and CD8+ T cells recognizing broader islet antigens into the pancreatic islets. The islet resident macrophages and infiltrated DCs, as well as the endothelium and the beta cells, express PD-L1. Diabetes doesn’t develop in NOD mice until about 20 weeks of age or later. Administration of anti-PD-1 antibody rapidly induces diabetes in the young mice showing a control phase established very early in the autoimmune process. Anti-PD-1 treatment induces a high level of islet leukocytes infiltration including CD4+ T cells and CD8+ T cells. The regulatory effect of PD-1 is involved in both CD4+ T cells which recognize self-peptides via H2g7MHC haplotype, as well as in CD8+ T cells. The islet resident macrophage is an essential component for the PD-1/PD-L1 regulatory pathway to take effect. In their absence, no diabetes develops even after anti-PD-1 treatment. The same observation is found in the NOD.Batf-3−/− mice. We suggest that the control mechanism takes place once T cells enter islets. To establish PD-1 regulation, IFNγ signaling is required probably via up-regulating PD-L1 expression on various types of cells in islets. Together, our study has explored the cellular basis of PD-1 in regulating diabetic autoimmunity in the NOD mouse.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.116.5
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Single-cell RNA sequencing of pancreatic islets reveals the complexity of autoimmune diabetes throughout its initiation and development
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 142.13-142.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 142.13-142.13
    Abstract: Type one diabetes (T1D) is a spontaneous autoimmune disease that results in pancreatic islet beta-cell death driven by diverse immune cells. However, molecular signatures of the leukocyte populations in T1D remain poorly defined. Here, using single-cell transcriptional analysis, we examined intra-islet leukocytes at various stages of disease: from its very early start, through its control phase and finally to the final effector stage. Early stages before clinical diagnosis are not accessible for human studies. We found that both CD4 and CD8 T cells showed heterogeneity at the initial stage of autoimmune inflammation and already contained effector cells. Moreover, the disease progression at all times was accompanied by regulatory sets establishing control mechanisms. In line with that, we also detected accumulation of anergic and exhaustion-associated phenotypes over time. Analysis of the islet macrophages showed substantial divergence, including novel population with anti-inflammatory and dead-cell clearance features. Autoimmune process resulted in polarization of islet macrophage into terminal pathogenic state via two-step activation program. While stage 1 marked by NF-kB activation was present in non-diabetic condition, stage 2 was inflammation-induced and had additional IFN-gamma activation. Interestingly, the final effector stages were not dominated by CD8 cytotoxic T cells but by pro-inflammatory macrophages. Overall, our analysis comprehensively describes stages of T1D on the basis of lymphoid and myeloid transcriptional activation programs, providing a detailed single-cell atlas of autoimmune diabetes initiation and development. Our findings will guide future studies in staging human T1D.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.142.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Systemic recognition of immunogenic insulin peptides promotes T cell diabetic autoimmunity in multiple lymphoid tissues
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 163.8-163.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 163.8-163.8
    Abstract: Recognition of insulin is essential for initiating autoimmune diabetes in the non-obese diabetic (NOD) mice; however, how this autoantigen is presented to pathogenic T cells remains unclear. In patients with type 1 diabetes, insulin autoantibodies (IAAs) are the earliest sign of disease. In NOD mice IAAs are detected before immune infiltration in islets, suggesting that insulin autoreactivity originates from peripheral lymphoid sites. This is confirmed by our previous studies showing formation of insulin-specific germinal centers in multiple lymph nodes accompanied by differentiation of cognate T follicular helper cells, indicating widespread insulin recognition. In this study, we used a two-photon imaging system that robustly and accurately detected presentation of the limited amounts of insulin peptide-MHC complexes. We demonstrate that insulin recognition by CD4 T cells takes place concomitantly in various lymph nodes, a process precisely guided by the specific epitope but not the autoimmune environment. Importantly, a unique set of insulin-reactive T cells specifically recognized free insulin peptides but not the conformational protein. During chronic antigen recognition, these T cells exhibited an effector but not exhaustion phenotype, manifested by transcriptional activation, metabolic reprogramming and enhanced pathogenicity. These findings reveal a unique pattern of insulin recognition that may account for its prime role in triggering autoimmune diabetes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.163.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Depletion of islet resident macrophages protects mice from type 1 diabetes
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 41.13-41.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 41.13-41.13
    Abstract: Tissue resident macrophages are found at birth in the islets of Langerhans of all strains of mice examined. To examine the macrophage’s role in islet homeostasis and diabetogenesis, we depleted the cells using a monoclonal antibody against the CSF-1 receptor. Depletion of islet macrophages in the C57BL/6 mouse strain for 2–6 weeks did not affect multiple parameters of homeostasis including glucose tolerance, insulin content, or whole islet transcriptome. In contrast, depletion of the islet macrophages in 3 week old diabetes-prone NOD mice led to multiple changes in the progression of disease. First, there was a reduction in CD4 T cells and dendritic cells that infiltrate islets at 4–6 weeks of age. Second, there was a reduction in the presentation of insulin-derived peptides to T cells by dispersed islet cells. Third, the development of autoimmune diabetes was significantly reduced. The protection from diabetes induced by anti-CSF-1 receptor antibody was effective even when treatment was started at 10 weeks of age, a time where NOD mice have significant infiltration in their islets. Despite the protection from diabetes, mice treated with anti-CSF-1 receptor antibody at both 3 and 10 weeks of age harbored extensive leukocytic infiltration into islets when examined at 20–40 weeks of age. Treatment with an anti-PD-1 antibody led to immediate diabetes progression in all of the long-term protected NOD mice. These results show that depletion of islet-resident macrophages limited the islet leukocytic infiltration in the early phase of diabetogenesis and also permitted the establishment of a long-lived protective regulatory milieu late in the disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.41.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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