10 ns PEFs induce a histological response linked to cell death and cytotoxic T-lymphocytes in an immunocompetent mouse model of peritoneal metastasis

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

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Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death

International Journal of Cancer ◽

10.1002/ijc.28070 ◽

2013 ◽

Vol 133 (3) ◽

pp. 624-636 ◽

Cited By ~ 134

Author(s):

James W. Hodge ◽

Charlie T. Garnett ◽

Benedetto Farsaci ◽

Claudia Palena ◽

Kwong-Yok Tsang ◽

...

Keyword(s):

Cell Death ◽

T Lymphocytes ◽

Tumor Cells ◽

Cytotoxic T Lymphocytes ◽

Immunogenic Cell Death ◽

Immunogenic Modulation

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The Role of Heterotypic DENV-specific CD8 + T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection

EBioMedicine ◽

10.1016/j.ebiom.2017.04.033 ◽

2017 ◽

Vol 20 ◽

pp. 202-216 ◽

Cited By ~ 9

Author(s):

Laura B. Talarico ◽

Juan P. Batalle ◽

Alana B. Byrne ◽

Jorge M. Brahamian ◽

Adrián Ferretti ◽

...

Keyword(s):

T Lymphocytes ◽

Virus Infection ◽

Mouse Model ◽

Dengue Virus ◽

Immunocompetent Mouse ◽

Dengue Virus Infection ◽

Cd8 T Lymphocytes

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HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death

Journal of Clinical Investigation ◽

10.1172/jci8707 ◽

2000 ◽

Vol 105 (10) ◽

pp. 1407-1417 ◽

Cited By ~ 71

Author(s):

Scott J. Brodie ◽

Bruce K. Patterson ◽

Deborah A. Lewinsohn ◽

Kurt Diem ◽

David Spach ◽

...

Keyword(s):

Cell Death ◽

T Lymphocytes ◽

Lymph Nodes ◽

Cytotoxic T Lymphocytes ◽

Hiv Replication

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Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

10.21203/rs.3.rs-41049/v3 ◽

2020 ◽

Author(s):

Daisuke Fujimori ◽

Jun Kinoshita ◽

Takahisa Yamaguchi ◽

Yusuke Nakamura ◽

Katsuya Gunjigake ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cell Line ◽

Peritoneal Metastasis ◽

Treatment Strategies ◽

M2 Macrophages ◽

Immunocompetent Mouse ◽

Immune Microenvironment ◽

Fibrous Stroma ◽

Immunocompetent Mice

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function

The Review of Diabetic Studies ◽

10.1900/rds.2009.6.43 ◽

2009 ◽

Vol 6 (1) ◽

pp. 43-53 ◽

Cited By ~ 4

Author(s):

Sarah Rasche ◽

Rhea Y. Busick ◽

Anthony Quinn

Keyword(s):

Cell Death ◽

T Lymphocytes ◽

Beta Cell ◽

Cytotoxic T Lymphocytes ◽

Loss Of Function ◽

Beta Cell Death ◽

Death And Loss

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Target cell death triggered by cytotoxic T lymphocytes: a target cell mutant distinguishes passive pore formation and active cell suicide mechanisms

Molecular and Cellular Biology ◽

10.1128/mcb.14.1.427-436.1994 ◽

1994 ◽

Vol 14 (1) ◽

pp. 427-436

Author(s):

D S Ucker ◽

J D Wilson ◽

L D Hebshi

Keyword(s):

Cell Death ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Target Cell ◽

Active Cell ◽

Death Process ◽

Target Cells ◽

Antigenic Stimulus ◽

Cell Suicide

The role of the target cell in its own death mediated by cytotoxic T lymphocytes (CTL) has been controversial. The ability of the pore-forming granule components of CTL to induce target cell death directly has been taken to suggest an essentially passive role for the target. This view of CTL-mediated killing ascribes to the target the single role of providing an antigenic stimulus to the CTL; this signal results in the vectoral degranulation and secretion of pore-forming elements onto the target. On the other hand, by a number of criteria, target cell death triggered by CTL appears fundamentally different from death resulting from membrane damage and osmotic lysis. CTL-triggered target cell death involves primary internal lesions of the target cell that reflect a physiological cell death process. Orderly nuclear disintegration, including lamin phosphorylation and solubilization, chromatin condensation, and genome digestion, are among the earliest events, preceding the loss of plasma membrane integrity. We have tested directly the involvement of the target cell in its own death by examining whether we could isolate mutants of target cells that have retained the ability to be recognized by and provide an antigenic stimulus to CTL while having lost the capacity to respond by dying. Here, we describe one such mutant, BW87. We have used this CTL-resistant mutant to analyze the mechanisms of CTL-triggered target cell death under a variety of conditions. The identification of a mutable target cell element essential for the cell death response to CTL provides genetic evidence that target cell death reflects an active cell suicide process similar to other physiological cell deaths.

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