CD4+ T cells kill Id+ B-lymphoma cells: FasLigand-Fas interaction is dominant in vitro but is redundant in vivo

2004 ◽  
Vol 53 (12) ◽  
pp. 1135-1145 ◽  
Author(s):  
Katrin U. Lundin ◽  
Valentina Screpanti ◽  
Hilde Omholt ◽  
Peter O. Hofgaard ◽  
Hideo Yagita ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells

scholarly journals Antigen-armed antibodies targeting B lymphoma cells effectively activate antigen-specific CD4+ T cells

Blood ◽  
2015 ◽  
Vol 125 (10) ◽  
pp. 1601-1610 ◽  
Author(s):  
Xiaojun Yu ◽  
Marta Ilecka ◽  
Emmalene J. Bartlett ◽  
Viktor Schneidt ◽  
Rauf Bhat ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
B Cell Receptors ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells ◽  
Key Points

Key PointsEpitopes in antigen-armed antibodies that target B-cell receptors are efficiently presented by B lymphoma cells to cytotoxic CD4+ T cells. Memory T cells activated by AgAbs ex vivo are able to kill targeted B lymphoma cells.

IL-6 Undergoes Transition from in vitro Autocrine Growth Factor to in vivo Growth Inhibitor of B Lymphoma Cells

1997 ◽  
Vol 4 (5) ◽  
pp. 201-207
Author(s):  
Dae-Ho Cho ◽  
Hyung-Sik Kang ◽  
Jung-Jae Ma ◽  
Sung-Sook Kim ◽  
Hwan-Mook Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Inhibitor ◽  
Autocrine Growth ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
Autocrine Growth Factor ◽  
B Lymphoma Cells ◽  
In Vivo Growth

177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo

2005 ◽  
Vol 32 (3) ◽  
pp. 269-278 ◽  
Author(s):  
Rosana B. Michel ◽  
Philip M. Andrews ◽  
Adriane V. Rosario ◽  
David M. Goldenberg ◽  
M. Jules Mattes
Keyword(s):  
Single Cell ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells ◽  
Cell Kill ◽  
Antibody Conjugates

scholarly journals Interleukin-6-knockdown of chimeric antigen receptor-modified T cells significantly reduces IL-6 release from monocytes

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Liqing Kang ◽  
Xiaowen Tang ◽  
Jian Zhang ◽  
Minghao Li ◽  
Nan Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Interleukin 6 ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
Car T Cell ◽  
B Lymphoma Cells ◽  
Car T

Abstract Background T cells expressing a chimeric antigen receptor (CAR) engineered to target CD19 can treat leukemia effectively but also increase the risk of complications such as cytokine release syndrome (CRS) and CAR T cell related encephalopathy (CRES) driven by interleukin-6 (IL-6). Here, we investigated whether IL-6 knockdown in CART-19 cells can reduce IL-6 secretion from monocytes, which may reduce the risk of adverse events. Methods Supernatants from cocultures of regular CART-19 cells and B lymphoma cells were added to monocytes in vitro, and the IL-6 levels in monocyte supernatants were measured 24 h later. IL-6 expression was knocked down in regular CART-19 cells by adding a short hairpin RNA (shRNA) (termed ssCART-19) expression cassette specific for IL-6 to the conventional CAR vector. Transduction efficiency and cell proliferation were measured by flow cytometry, and cytotoxicity was measured by evaluating the release of lactate dehydrogenase into the medium. Gene expression was assessed by qRT-PCR and RNA sequencing. A xenograft leukemia mouse model was established by injecting NOD/SCID/γc-/- mice with luciferase-expressing B lymphoma cells, and then the animals were treated with regular CART-19 cells or ssCART-19. Tumor growth was assessed by bioluminescence imaging. Results Both recombinant IL-6 and CART-19 derived IL-6 significantly triggered IL-6 release by monocytes. IL-6 knockdown in ssCART-19 cells dramatically reduced IL-6 release from monocytes in vitro stduy. In vivo study further demonstrated that the mice bearing Raji cells treated with ssCART-19 cells showed significant lower IL-6 levels in serum than those treated with regular CART-19 cells, but comparable anti-tumor efficacy between the animal groups. Conclusion CAR T-derived IL-6 is one of the most important initiators to amplify release of IL-6 from monocytes that further drive sCRS development. IL-6 knockdown in ssCART-19 cells by shRNA technology provide a promising strategy to improve the safety of CAR T cell therapy.

Therapeutic effect of idiotype-specific CD4+ T cells against B-cell lymphoma in the absence of anti-idiotypic antibodies

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 605-612 ◽  
Author(s):  
Katrin U. Lundin ◽  
Peter O. Hofgaard ◽  
Hilde Omholt ◽  
Ludvig A. Munthe ◽  
Alexandre Corthay ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Lymphoma ◽  
Severe Combined Immunodeficiency ◽  
Tumor Development ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells

AbstractImmunoglobulin (Ig) variable (V) region idiotypes (Id's) are highly tumor-specific antigens produced by B-lymphoma cells and are promising targets for immunotherapy. Id vaccination has proven effective in experimental mouse models and may possibly prevent recurrence of B lymphomas in humans. It has previously been shown that anti-Id antibodies protect against B-cell lymphoma in the absence of T cells. We here demonstrate in a T-cell–receptor transgenic mouse model that the contrary is also true: Id-specific CD4+ T cells can protect against Id+ B-lymphoma cells in the absence of B cells, antibodies, and CD8+ T cells. Moreover, Id-specific CD4+ T cells have a curative potential since they could be transferred as late as 17 days after subcutaneous tumor cell injection of severe combined immunodeficiency (SCID) mice and still abrogate tumor development in about 50% of mice. Such mice undergo an acute inflammatory swelling with infiltration of neutrophils at the site of tumor injection, which subsides over weeks, with some mice cured and delayed emergence of lymphomas in other mice. Adoptively transferred CD4+ T cells accumulated in the tumor and were activated (CD69+). In vitro experiments demonstrated that memory, but not naive, Id-specific CD4+ T cells kill Id+ B-lymphoma cells. The results show that Id-specific CD4+ T cells, in the absence of antibodies home to subcutaneous Id+ B lymphoma, become activated, induce inflammation, and prevent tumor development.

IL-6 undergoes transition from in vitro autocrine growth factor to in vivo growth inhibitor of B lymphoma cells

1997 ◽  
Vol 4 (5) ◽  
pp. 201-207 ◽  
Author(s):  
Dae-Ho Cho ◽  
Hyung-Sik Kang ◽  
Jung-Jae Ma ◽  
Sung-Sook Kim ◽  
Hwan-Mook Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Inhibitor ◽  
Autocrine Growth ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
Autocrine Growth Factor ◽  
B Lymphoma Cells ◽  
In Vivo Growth

scholarly journals Interleukin-6-knockdown of chimeric antigen receptor-modified T cells significantly reduces IL-6 release from monocytes

2020 ◽  
Author(s):  
Liqing Kang ◽  
Xiaowen Tang ◽  
Jian Zhang ◽  
Minghao Li ◽  
Nan Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Chimeric Antigen Receptor ◽  
Interleukin 6 ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells ◽  
Car T

Abstract Background T cells expressing a chimeric antigen receptor (CAR) engineered to target CD19 can treat leukemia effectively but also increase the risk of complications such as cytokine release syndrome (CRS) and CAR T cell related encephalopathy (CRES) driven by interleukin-6 (IL-6). Here, we investigated whether IL-6 knockdown in CART-19 cells can reduce IL-6 secretion from monocytes, which may reduce the risk of adverse events. Methods Supernatants from cocultures of regular CART-19 cells and B lymphoma cells were added to monocytes in vitro, and the IL-6 levels in monocyte supernatants were measured 24 h later. IL-6 expression was knocked down in regular CART-19 cells by adding a short hairpin RNA (shRNA) (termed ssCART-19) expression cassette specific for IL-6 to the conventional CAR vector. Transduction efficiency and cell proliferation were measured by flow cytometry, and cytotoxicity was measured by evaluating the release of lactate dehydrogenase into the medium. Gene expression was assessed by qRT-PCR and RNA sequencing. A xenograft leukemia mouse model was established by injecting NOD/SCID/γc-/- mice with luciferase-expressing B lymphoma cells, and then the animals were treated with regular CART-19 cells or ssCART-19. Tumor growth was assessed by bioluminescence imaging. Results Both recombinant IL-6 and activated regular CART-19 cells expressing IL-6 triggered IL-6 release by monocytes. IL-6 knockdown in ssCART-19 cells dramatically reduced IL-6 release from monocytes without reducing cytotoxic activity. Mice treated with ssCART-19 cells showed lower IL-6 levels in the serum than mice treated with regular CART-19 cells, but tumor growth and survival were similar between the animal groups. Conclusion IL-6 released from activated CAR T cells may be one of the main initiators of the release of IL-6 from monocytes that can drive CRS. IL-6 knockdown in ssCART-19 cells reduces monocyte release of IL-6 both in vitro and in vivo without affecting antitumor efficacy. The IL-6 knockdown strategy may provide a useful and promising way to improve the safety of CAR T cell therapy.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

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