Fas-ligand-mediated lysis of erbB-2-expressing tumour cells by redirected cytotoxic T lymphocytes

1999 ◽  
Vol 47 (5) ◽  
pp. 278-286 ◽  
Author(s):  
Nicole M. Haynes ◽  
Mark J. Smyth ◽  
Michael H. Kershaw ◽  
Joseph A. Trapani ◽  
Phillip K. Darcy
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Tumour Cells

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

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.

Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2352-2355 ◽  
Author(s):  
Masaki Yasukawa ◽  
Hideki Ohminami ◽  
Junko Arai ◽  
Yoshihito Kasahara ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Hla Antigens ◽  
Peripheral Blood Lymphocytes ◽  
Messenger Rnas ◽  
Granule Exocytosis ◽  
Ligand System ◽  
Concanamycin A ◽  
Main Pathway

We investigated the cytotoxicity mechanisms of alloantigen-specific human CD4+ and CD8+ cytotoxic T lymphocytes (CTLs) using cells from family members with the Fas gene mutation. Alloantigen-specific CD4+ and CD8+ CTL bulk lines and clones were generated from 2 individuals by stimulation of their peripheral blood lymphocytes with allogeneic Fas−/− or Fas+/− cell lines that were established from B-lymphocytes of a patient with Fas deficiency and her mother, respectively. Both CD4+ and CD8+CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas−/− and Fas+/− cells to almost the same degree. The cytotoxicity of CD4+ and CD8+ CTLs appeared to be Ca2+-dependent and was completely inhibited by concanamycin A, an inhibitor of perforin-mediated cytotoxicity. Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand, perforin, and granzyme B were all detected in these CD4+CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4+ CTL clones that showed Fas-independent cytotoxicity were TH0, as determined by their cytokine production profile. These data, obtained with the use of a novel experimental system, clearly show that the main pathway of cytotoxicity mediated by alloantigen-specific human CD4+as well as by CD8+ CTLs is granule exocytosis, and not the Fas/Fas ligand system.

Soluble HLA class I/CD8 ligation triggers apoptosis in EBV-specific CD8+ cytotoxic T lymphocytes by Fas/Fas-ligand interaction

2000 ◽  
Vol 61 (12) ◽  
pp. 1347-1351 ◽  
Author(s):  
Paola Contini ◽  
Massimo Ghio ◽  
Andrea Merlo ◽  
Sabrina Brenci ◽  
Gilberto Filaci ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Hla Class I ◽  
Class I ◽  
Ligand Interaction ◽  
Soluble Hla

scholarly journals Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4677-4684 ◽  
Author(s):  
Gianpietro Dotti ◽  
Barbara Savoldo ◽  
Martin Pule ◽  
Karin C. Straathof ◽  
Ettore Biagi ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Cellular Therapy ◽  
Effector Memory ◽  
Adoptive Cellular Therapy ◽  
Barr Virus ◽  
Epstein Barr ◽  
Induced Apoptosis

Abstract Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Faslow and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (Blood. 2005;105:4677-4684)

Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2352-2355 ◽  
Author(s):  
Masaki Yasukawa ◽  
Hideki Ohminami ◽  
Junko Arai ◽  
Yoshihito Kasahara ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Hla Antigens ◽  
Peripheral Blood Lymphocytes ◽  
Messenger Rnas ◽  
Granule Exocytosis ◽  
Ligand System ◽  
Concanamycin A ◽  
Main Pathway

Abstract We investigated the cytotoxicity mechanisms of alloantigen-specific human CD4+ and CD8+ cytotoxic T lymphocytes (CTLs) using cells from family members with the Fas gene mutation. Alloantigen-specific CD4+ and CD8+ CTL bulk lines and clones were generated from 2 individuals by stimulation of their peripheral blood lymphocytes with allogeneic Fas−/− or Fas+/− cell lines that were established from B-lymphocytes of a patient with Fas deficiency and her mother, respectively. Both CD4+ and CD8+CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas−/− and Fas+/− cells to almost the same degree. The cytotoxicity of CD4+ and CD8+ CTLs appeared to be Ca2+-dependent and was completely inhibited by concanamycin A, an inhibitor of perforin-mediated cytotoxicity. Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand, perforin, and granzyme B were all detected in these CD4+CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4+ CTL clones that showed Fas-independent cytotoxicity were TH0, as determined by their cytokine production profile. These data, obtained with the use of a novel experimental system, clearly show that the main pathway of cytotoxicity mediated by alloantigen-specific human CD4+as well as by CD8+ CTLs is granule exocytosis, and not the Fas/Fas ligand system.

Cytokine-Based Tumor Cell Vaccine Is Equally Effective Against Parental and Isogenic Multidrug-Resistant Myeloma Cells: The Role of Cytotoxic T Lymphocytes

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1831-1837 ◽  
Author(s):  
Alexander A. Shtil ◽  
Joel G. Turner ◽  
John Durfee ◽  
William S. Dalton ◽  
Hua Yu
Keyword(s):  
T Lymphocytes ◽  
Tumor Cell ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Multidrug Resistant ◽  
Interleukin 12 ◽  
Cell Vaccine ◽  
Tumor Cell Vaccine ◽  
Gm Csf ◽  
Immune Therapies

Tumor cells that survive initial courses of chemotherapy may do so by acquiring a multidrug-resistant phenotype. This particular mechanism of drug resistance may also confer resistance to physiological effectors of apoptosis that could potentially reduce the efficacy of immune therapies that use these pathways of cell death. We have previously demonstrated high efficacy for a cytokine-based tumor cell vaccine in a murine MPC11 myeloma model. In the present study, the effects of this vaccination were compared in MPC11 cells and their isogenic sublines selected for mdr1/P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Immunization with MPC11 cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) led to long-lasting protection of mice against subcutaneous (sc) challenge with both parental cells or their MDR variants. Similarly, immunization with GM-CSF/IL-12–transfected MDR sublines caused rejection of transplantation of both parental cells and the MDR sublines. Whereas MPC11 cells and their MDR variants were resistant to APO-1/CD95/Fas ligand, the immunization generated potent granzyme B/perforin-secreting cytotoxic T lymphocytes (CTLs) that were similarly effective against both parental and isogenic MDR cells. We conclude that MDR mediated bymdr1/Pgp did not interfere with lysis by pore-forming CTLs. Immunotherapy based on pore-forming CTLs may be an attractive approach to the treatment of drug-resistant myeloma.

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