Activation of lymphokine genes during stimulation of cloned T cells

Herold, Kevan C.; Lancki, David W.; Dunn, Daniel E.; Arai, Kohei; Fitch, Frank W.

doi:10.1002/eji.1830161211

Cited by 17 publications

(7 citation statements)

References 35 publications

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“…With TPA/ionomycin, IL-13 mRNA peaked at 4 h, whereas the protein peak occurred at 8 h. Stimulation with a-CD3/a-CD28 caused a much slower increase which remained at high levels throughout the observation period. Similar kinetics have been observed for IL-2 (Herold et al, 1986).…”

Section: Discussionsupporting

confidence: 83%

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Pahl

Zhang

Kuss³

et al. 2002

British J Pharmacology

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1 IL-13 is an important mediator in in¯ammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not wellcharacterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4 + T cells. 2 Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ ionomycin. However, stimulation by a-CD3/a-CD28 led to an enhanced IL-13 synthesis. 3 NF-kB inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more eectively after TPA/ionomycin stimulation. After a-CD3/a-CD28 stimulation, only 300 mM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally eective after a-CD3/a-CD28 and TPA/ionomycin stimulation. 4 p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very eectively, whereas a-CD3/a-CD28 stimulated IL-13 induction was resistant to this drug. 5 These results were con®rmed in puri®ed CD4 + T cells. In dierence to PBMCs a-CD3/a-CD28 stimulated IL-13 synthesis was eectively inhibited by CsA, FK-506 and U0126. 6 Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the ®rst time that inhibition of the MEK ± ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg 71 U0126 reduced lung eosinophilia in ovalbuminchallenged Brown Norway rats by 44%. 7 These results demonstrate that dierent signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.

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Section: Discussionsupporting

confidence: 83%

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Pahl

Zhang

Kuss³

et al. 2002

British J Pharmacology

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“…In order to see whether CTL 49 was able to express genes coding for these cytokines and to test whether cytokine mRNAs levels were susceptible to modulation following TCR engagement [13,32] the mRNA levels of unstimulated CTL 49 cells (i. e. cells isolated 6 days after the last addition of irradiated VSKB-LCL and cultured in the presence of rIL-2) were compared with the mRNA levels seen at different intervals after stimulation with anti-CD3 mAb. As shown in Fig.…”

Section: Expression and Inducibility Of Tnfc~- Tnf~-and Ifnyspecificmentioning

confidence: 99%

T lymphocytes can mediate lysis of autologous melanoma cells by multiple mechanisms: Evidence with a single T cell clone

Mazzocchi

Anichini

Castelli

et al. 1990

Cancer Immunol Immunother

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The specificity analysis of a CD3+, WT31+, CD8+ cytotoxic T lymphocyte (CTL) clone (CTL 49), isolated from peripheral blood lymphocytes of a melanoma patient (no. 665) after mixed lymphocyte culture with an HLA-A2+ allogeneic lymphoblastoid cell line (VSKB-LCL), revealed that CTL 49 could lyse, in addition to HLA-A2+ lines, autologous HLA-A2- melanoma (Me665/2) and K562 targets. Killing of VSKB-LCL, but not of Me665/2, could be inhibited by anti-CD3 and by anti-HLA-A2 antibodies or by modulation of the CD3 complex. Cold-target competition studies showed that K562, but not VSKB-LCL, could compete with Me665/2 for lysis by CTL 49. However, unlike K562, Me665/2 could be lysed by CTL 49 in a Ca2(+)-independent fashion in 4 h and 18 h assays. CTL 49 expressed mRNA specific for tumor necrosis factor (TNF alpha) and, to a lesser extent, for lymphotoxin (TNF beta). Exposure of the clone to anti-CD3 antibodies induced the expression of interferon(IFN)-gamma-specific mRNA. Antibodies to TNF alpha, TNF beta and IFN reduced the lysis of Me665/2, but not of K562, by CTL 49 in 18-h cytotoxic assays. Antibodies to TNF alpha and to IFN gamma almost completely inhibited the lysis seen on Me665/2 (but not on K562), in 96-h assays, by supernatants isolated from VSKB-LCL- or anti-CD3-stimulated CTL 49 cells. Taken together, these data indicate that major-histocompatibility-complex-independent lysis of autologous tumor cells and of natural killer reference targets by the same alloreactive T cell clone are activities related at the level of target recognition but distinct at the level of the lytic hit. Thus, efficient lysis of autologous tumor cells results from a complex mechanism based upon direct effector-target interaction as well as on cytokine-mediated cytolytic effects.

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“…This activation induces the production of lymphokines that in turn lead to activation of the antigen-presenting B cell. The overall specificity of the interaction is preserved by the requirement for antigen recognition in order to activate lymphokine production by Th cells [2], and by the fact that resting B cells do not respond to Th cell-derived B cell-activating factors [3-51. "Bystander" B cell activation is considered to result from the proximity to an activated Th cell of B cells that have been preactivated through encounter either with antigen, or with other surface immunoglobulin (s1g)-ligating agents [ l , 6,71.…”

Section: Introductionmentioning

confidence: 99%

A noncognate interaction with anti‐receptor antibody‐activated helper T cells induces small resting murine B cells to proliferate and to secrete antibody

Owens

1988

Eur J Immunol

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Culture of small resting allogeneic B cells (of an irrelevant haplotype) with two clones of T helper (Th) cells that were activated by the F23.1 anti-T cell receptor antibody led to the activation of B cells to proliferate and to secrete antibody. Th cell supernatants by themselves had no effect on resting B cells (even in the presence of intact F23.1 antibody), but could induce antibody secretion by anti-Ig-preactivated B cells. Both F23.1+ clones (E9.D4 and 4.35F2) and one F23.1- clone (D2.2) could synergize with supernatants from activated E9.D4 T cells to induce B cell activation. F(ab')2 fragments of F23.1 induced E9.D4 to activate B cells as efficiently as intact F23.1 and B cell populations that had been incubated with F23.1 were not activated when cultured with E9.D4, although T cells recognized cell-presented F23.1 and were weakly activated. Reduction of the density of F23.1 adsorbed to plastic resulted in weak T cell activation, and these T cells did not induce B cell responses. Haptenated B cell populations, although recognized by E9.D4, were not activated. Separation of T and B cells by a 0.4-micron membrane prevented T-dependent B cell activation, although Th cell-derived B cell-activating lymphokines would be assayed across these membranes. These results suggest a polyclonal noncognate B cell activation that depends on physical contact between B cells and activated T cells. The requirement for a cognate interaction of Th with B cells for the production and delivery of B help can therefore be overcome by activating Th cells with high densities of T cell receptor ligands.

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Activation of lymphokine genes during stimulation of cloned T cells

Cited by 17 publications

References 35 publications

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

Regulation of IL‐13 synthesis in human lymphocytes: implications for asthma therapy

T lymphocytes can mediate lysis of autologous melanoma cells by multiple mechanisms: Evidence with a single T cell clone

A noncognate interaction with anti‐receptor antibody‐activated helper T cells induces small resting murine B cells to proliferate and to secrete antibody

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