scholarly journals Transfer of dendritic cells (DC) ex vivo stimulated with interferon-gamma (IFN-γ) down-modulates autoimmune diabetes in non-obese diabetic (NOD) mice

1999 ◽  
Vol 117 (1) ◽  
pp. 38-43 ◽  
Author(s):  
SHINOMIYA ◽  
FAZLE AKBAR ◽  
SHINOMIYA ◽  
ONJI
Keyword(s):  
Dendritic Cells ◽  
Interferon Gamma ◽  
Ex Vivo ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Ifn Γ

scholarly journals Epigenetic reprogramming ameliorates type 1 diabetes by decreasing the generation of Th1 and Th17 subsets and restoring self-tolerance in CD4+ T cells

2021 ◽  
Author(s):  
Vasu Patel ◽  
Arathi Jayaraman ◽  
Sundararajan Jayaraman
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Ex Vivo ◽  
Autoimmune Diabetes ◽  
Trichostatin A ◽  
Nod Mice ◽  
Th1 Cells ◽  
Dependent Manner ◽  
Self Tolerance ◽  
Ifn Γ

The histone modifier Trichostatin A (TSA) ameliorated diabetes and repressed IFN-γ and IL-17A expression in prediabetic female NOD mice. Purified CD4+ cells could be polarized ex vivo into Th1 and Th17 subsets, which comparably transferred diabetes into NOD.scid mice. Polarized Th1 cells were devoid of IL-17A-producing cells and did not transdifferentiate into Th17 cells in an immunodeficient environment. However, Th17 cells had contaminant Th1 cells, which expressed IFN-γ upon adoptive transfer into lymphopenic recipients. Notably, TSA treatment abrogated the transfer of diabetes by CD4+ T-cells cultured under Th1 or Th17 polarizing conditions accompanied by the absence of Ifng and Il17a expression in NOD.scid recipients. Significantly, the histone modifier restored the ability of CD4+ but not CD8+ T-cells to undergo CD3-mediated apoptosis ex vivo in a caspase-dependent manner. Thus, the histone modifier afforded protection against autoimmune diabetes by negative regulation of signature lymphokines and restitution of self-tolerance in CD4+ T cells.

scholarly journals Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

2008 ◽  
Vol 127 (2) ◽  
pp. 176-187 ◽  
Author(s):  
Rémi J. Creusot ◽  
Shahriar S. Yaghoubi ◽  
Keiichi Kodama ◽  
Demi N. Dang ◽  
Vu H. Dang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Targeted Therapy ◽  
Autoimmune Diabetes ◽  
Nod Mice

scholarly journals TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2417 ◽  
Author(s):  
Tram N. Dao ◽  
Sagar Utturkar ◽  
Nadia Atallah Lanman ◽  
Sandro Matosevic
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Dysfunction ◽  
Nk Cell Receptors ◽  
Ifn Γ

Among natural killer (NK) cell receptors, the T-cell immunoglobulin and mucin-containing domain (TIM-3) has been associated with both inhibitory and activating functions, depending on context and activation pathway. Ex vivo and in vitro, expression of TIM-3 is inducible and depends on activation stimulus. Here, we report that TIM-3 expression can be downregulated on NK cells under specific conditions. When NK cells are exposed to cancer targets, they synergize with stimulation conditions to induce a substantial decrease in TIM-3 expression on their surface. We found that such downregulation occurs following prior NK activation. Downregulated TIM-3 expression correlated to lower cytotoxicity and lower interferon gamma (IFN-γ) expression, fueling the notion that TIM-3 might function as a benchmark for human NK cell dysfunction.

Systemic Production of Interferon-Gamma Inducing Factor (IGIF) Versus Local IFN-γ Expression Involved in the Development of Th1 Insulitis in NOD Mice

1997 ◽  
Vol 10 (3) ◽  
pp. 251-256 ◽  
Author(s):  
Helga Rothe ◽  
Tutsomu Hibino ◽  
Yasuhiro Itoh ◽  
Hubert Kolb ◽  
Stephan Martin
Keyword(s):  
Interferon Gamma ◽  
Nod Mice ◽  
Ifn Γ

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

2015 ◽  
Vol 21 (14) ◽  
pp. 1811-1822 ◽  
Author(s):  
Felix Luessi ◽  
Stefan Kraus ◽  
Bettina Trinschek ◽  
Steffen Lerch ◽  
Robert Ploen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Direct Effects ◽  
Quantitative Analyses ◽  
Ifn Γ ◽  
Multiple Sclerosis Patients ◽  
Antigen Presenting

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

Detailed modulation of phenotypes and functions of bone marrow dendritic cells (BMDCs) by interferon-gamma (IFN-γ)

2013 ◽  
Vol 17 (2) ◽  
pp. 366-372 ◽  
Author(s):  
Ming Xue ◽  
Linlin Zhu ◽  
Yiming Meng ◽  
Li Wang ◽  
Haiyan Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Interferon Gamma ◽  
Ifn Γ

scholarly journals The Injury Response to DNA Damage Promotes Anti-Tumor Immunity

2020 ◽  
Author(s):  
Ganapathy Sriram ◽  
Lauren Milling ◽  
Jung-Kuei Chen ◽  
Wuhbet Abraham ◽  
Erika D. Handly ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Ex Vivo ◽  
Injured Cell ◽  
Ifn Γ

ABSTRACTInhibition of immune checkpoints has shown promising results in the treatment of certain tumor types. However, the majority of cancers do not respond to immune checkpoint inhibition (ICI) treatment, indicating the need to identify additional modalities that enhance the response to immune checkpoint blockade. In this study, we identified a tumor-tailored approach using ex-vivo DNA damaging chemotherapy-treated tumor cells as a live injured cell adjuvant. Using an optimized ex vivo system for dendritic cell-mediated T-cell IFN-γ induction in response to DNA-damaged tumor cells, we identified specific dose-dependent treatments with etoposide and mitoxantrone that markedly enhance IFN-γ production by T-cells. Unexpectedly, the immune-enhancing effects of DNA damage failed to correlate with known markers of immunogenic cell death or with the extent of apoptosis or necroptosis. Furthermore, dead tumor cells alone were not sufficient to promote DC cross-presentation and induce IFN-γ in T-cells. Instead, the enhanced immunogenicity resided in the fraction of injured cells that remained alive, and required signaling through the RIPK1, NF-kB and p38MAPK pathways. Direct in vivo translation of these findings was accomplished by intra-tumoral injection of ex vivo etoposide-treated tumor cells as an injured cell adjuvant, in combination with systemic anti-PD1/CTLA4 antibodies. This resulted in increased intra-tumoral CD103+ dendritic cells and circulating tumor antigen-specific CD8+ T-cells, leading to enhanced anti-tumor immune responses and improved survival. The effect was abrogated in BATF3-deficient mice indicating that BATF3+ DCs are required for appropriate T-cell stimulation by live but injured DNA-damaged tumor cells. Notably, injection of the free DNA-damaging drug directly into the tumor failed to elicit such an enhanced anti-tumor response as a consequence of simultaneous damage to dendritic cells and T-cells. Finally, the DNA damage induced injured cell adjuvant and systemic ICI combination, but not ICI alone, induced complete tumor regression in a subset of mice who were then able to reject tumor re-challenge, indicating induction of a long-lasting anti-tumor immunological memory by the injured cell adjuvant treatment in vivo.

scholarly journals Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice

2020 ◽  
Vol 117 (49) ◽  
pp. 31319-31330
Author(s):  
Hao Hu ◽  
Pavel N. Zakharov ◽  
Orion J. Peterson ◽  
Emil R. Unanue
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Autoimmune Diabetes ◽  
Critical Role ◽  
Nod Mice ◽  
Checkpoint Blockade ◽  
Cellular Interactions ◽  
Activated T Cells ◽  
Acute Diabetes ◽  
Ifn Γ

Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.

scholarly journals Freshly Isolated Peyer's Patch, but Not Spleen, Dendritic Cells Produce Interleukin 10 and Induce the Differentiation of T Helper Type 2 Cells

1999 ◽  
Vol 190 (2) ◽  
pp. 229-240 ◽  
Author(s):  
Akiko Iwasaki ◽  
Brian Lee Kelsall
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Ex Vivo ◽  
T Helper ◽  
Phenotypic Analysis ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Ifn Γ

Orally administered antigens often generate immune responses that are distinct from those injected systemically. The role of antigen-presenting cells in determining the type of T helper cell response induced at mucosal versus systemic sites is unclear. Here we examine the phenotypic and functional differences between dendritic cells (DCs) freshly isolated from Peyer's patches (PP) and spleen (SP). Surface phenotypic analysis of CD11c+ DC populations revealed that PP DCs expressed higher levels of major histocompatibility complex class II molecules, but similar levels of costimulatory molecules and adhesion molecules compared with SP DCs. Freshly isolated, flow cytometrically sorted 98–100% pure CD11c+ DC populations from PP and SP were compared for their ability to stimulate naive T cells. First, PP DCs were found to be much more potent in stimulating allogeneic T cell proliferation compared with SP DCs. Second, by using naive T cells from ovalbumin peptide–specific T cell receptor transgenic mice, these ex vivo DCs derived from PP, but not from SP, were found to prime for the production of interleukin (IL)-4 and IL-10 (Th2 cytokines). In addition, PP DCs were found to prime T cells for the production of much lower levels of interferon (IFN)-γ (Th1) compared with SP DCs. The presence of neutralizing antibody against IL-10 in the priming culture dramatically enhanced IFN-γ production by T cells stimulated with PP DCs. Furthermore, stimulation of freshly isolated PP DCs via the CD40 molecule resulted in secretion of high levels of IL-10, whereas the same stimulus induced no IL-10 secretion from SP DCs. These results suggest that DCs residing in different tissues are capable of inducing distinct immune responses and that this may be related to the distinct cytokines produced by the DCs from these tissues.

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