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1.
Øystein Bruserud 《Cancer immunology, immunotherapy : CII》1998,46(4):221-228
T lymphocytes are important both for the host defence against infections and probably also as antileukaemic effector cells
in patients with acute leukaemia. To investigate the T lymphocyte cytokine repertoire of clonogenic T lymphocytes, CD4+ and CD8+ T lymphocyte clones were prepared from acute leukaemia patients with chemotherapy-induced cytopenia (leucocytes <0.5×109/l). A majority of both CD4+ and CD8+ clones secreted detectable interleukin-2 (IL-2), IL-10, IL-13, granulocyte/macrophage-colony-stimulating factor and interferon
γ (IFNγ) in response to phytohaemagglutinin + accessory cells (Epstein-Barr-virus-transformed B cell line, 80-Gy-irradiated).
The CD4+ clones showed significantly higher levels of IL-10 secretion than the CD8+ clones. Decreased levels of IL-2, IL-13 and IFNγ were observed when acute myelogenous leukaemia (AML) blasts were used instead
of cells from the B cell line as accessory cells during phytohaemagglutinin activation, but the differences in IL-13 and IFNγ
levels were reversed by addition of exogenous IL-2. On the basis of these results we conclude: (i) the remaining clonogenic
T lymphocytes derived from acute leukaemia patients with therapy-induced leucopenia can respond to activation with a broad
cytokine response, and T-cell-derived cytokines may then contribute to cytokine responses during complicating infections in
these patients; (ii) although T cells can modulate AML blast functions and mediate antileukaemic effects, the leukaemia blasts
will also modulate T cell functions and alter the cytokine profile of activated T lymphocytes.
Received: 6 November 1997 / Accepted: 5 March 1998 相似文献
2.
Øystein Bruserud Laila Mentzoni Brynjar Foss Jann Bergheim Sigbjørn Berentsen Ingerid Nesthus 《Cancer immunology, immunotherapy : CII》1997,43(5):275-282
Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more
than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine
secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFNγ) secretion. Interleukin-1 (IL-1) receptor antagonist and IL-2-neutralizing
antibodies decreased IFNγ secretion. Exogenous IL-1β, IL-2 and IL-7 increased allostimulated IFNγ secretion, whereas decreased
levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition
IFNγ -neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both
CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population
of native, cytokine-secreting leukaemia blasts, and (ii) IFNγ released during this response can modulate the function of allogeneic
AML blasts.
Received: 4 June 1996 / Accepted: 15 October 1996 相似文献
3.
T cell clones (CD4+CD8–TCRαβ+γδ–) derived from bone marrow transplant recipients were stimulated with phytohaemagglutinin (PHA) +interleukin-2 (IL-2) in the
presence of irradiated (50 Gy) peripheral blood mononuclear cells (PBMC) derived from acute leukaemia patients(leukaemic PBMC
containing more than 95% blast cells). Leukaemic PBMC could function as accessory cells during mitogenic T cell activation
resulting in both T cell proliferation and a broad T cell cytokine response [IL-3, IL-4, IL-10, granulocyte/macrophage-colony-stimulating
factor (GM-CSF) tumour necrosis factor α (TNFα) and interferon γ (IFNγ) secretion]. Blockade of IL-1 effects by adding IL-1
receptor antagonist together with PHA+IL-2+leukaemia blasts increased T cell proliferation, whereas IL-6-neutralizing antibodies
did not alter T cell proliferation. A qualitatively similar T cell cytokine response and a similar cytokine profile (highest
levels detected for GM-CSF and IFNγ) were detected when normal polyclonal T cell lines were stimulated with PHA in the presence
of non-irradiated leukaemic PBMC. When leukaemic PBMC derived from 18 acute myelogenous leukaemia patients were cultured with
PHA and cells from a polyclonal T cell line, increased concentrations of the T cell cytokines IFNγ and IL-4 were detected
for all patients. We conclude that T cell activation resulting in proliferation and a broad cytokine response can take place
in the presence of excess acute myelogenous leukaemia blasts.
Received: 30 November 1995 / Accepted: 9 January 1996 相似文献
4.
Fas (CD95/Apo-1) exists both in membrane-bound and in biologically active soluble (s) forms. Ligation of membrane-expressed
Fas can induce apoptosis, and Fas-mediated signaling seems to be involved in T-cell-induced apoptosis of human acute myelogenous
leukemia (AML) blasts. The local release of sFas by AML blasts may then function as a protective mechanism by competing with
membrane-bound Fas for binding sites on the common Fas ligand (FasL). sFas was released by AML blasts during in vitro culture,
and this release was modulated by several cytokines that can be secreted by activated T cells. Increased levels of sFas could
be detected during in vitro activation of T cells in the presence of native AML accessory cells, and this was observed both
for (i) mitogenic activation of CD4+ and CD8+ T cell clones derived from acute leukemia patients with therapy-induced leukopenia and (ii) allostimulated activation of
T cells derived from normal donors. However, local in vivo levels of sFas will also be influenced by variations in systemic
levels. High serum levels of sFas were detected in acute leukemia patients during chemotherapy-induced cytopenia, but these
levels decreased during complicating bacterial infections. In contrast, serum levels of sFasL were normal in leukopenic patients.
The present results support the hypothesis that local release of sFas can function as a protective mechanism against AML-reactive
T cells, but the effects of this local release are, in addition, modulated by variations in systemic levels of sFas (but not
sFasL).
Received: 9 March 2000 / Accepted: 25 May 2000 相似文献
5.
The ability of acute myelogenous leukemia (AML) blasts to mediate costimulatory signals during T lymphocyte activation was investigated in an experimental model where monoclonal T cell populations were stimulated with standardized activation signals (anti-CD3, anti-CD2, and anti-CD28 monoclonal antibodies and phytohemagglutinin). Proliferative T cell responses were detected for all AML patients (n = 16) when irradiated leukemia blasts were used as accessory cells during activation. T cell cytokine release was also observed for all patients when nonirradiated AML accessory cells were used, and for most patients a broad cytokine response (interleukin (IL) 2, IL4, IL10, IL13, and interferon-gamma) was detected. However, both T cell proliferation and cytokine release showed a wide variation among AML patients, and T cell responsiveness was in addition dependent both on the nature of the activation signal and on differences between individual T cell clones. The accessory cell function of AML blasts showed no correlation with the release of any single immunomodulatory soluble mediator (IL1beta, IL6, TNF-alpha, soluble IL2 receptors) or the expression of any particular adhesion/costimulatory membrane molecule (CD54, CD58, CD80, and CD86) by the blasts. However, blocking studies with anti-CD58 and anti-CD80/86 monoclonal antibodies demonstrated that both pathways can be involved when AML blasts are used as accessory cells, but the relative importance and the final effects of signaling through these pathways differ between AML populations. Although there is a wide interpatient variation, we conclude that for a majority of patients the native AML blasts can mediate adequate costimulatory signals needed for accessory cell-dependent T cell activation. 相似文献
6.
Qiao Lu Meixing Yu Chongyang Shen Xiaoping Chen Ting Feng Yongchao Yao Jinrong Li Hong Li Wenwei Tu 《PloS one》2014,9(12)
Human induced pluripotent stem cells (hiPSCs) have potential applications in cell replacement therapy and regenerative medicine. However, limited information is available regarding the immunologic features of iPSCs. In this study, expression of MHC and T cell co-stimulatory molecules in hiPSCs, and the effects on activation, proliferation and cytokine production in allogeneic human peripheral blood mononuclear cells were examined. We found that no-integrate hiPSCs had no MHC-II and T cell co-stimulatory molecules expressions but had moderate level of MHC-I and HLA-G expressions. In contrast to human skin fibroblasts (HSFs) which significantly induced allogeneic T cell activation and proliferation, hiPSCs failed to induce allogeneic CD45+ lymphocyte and CD8+ T cell activation and proliferation but could induce a low level of allogeneic CD4+ T cell proliferation. Unlike HSFs which induced allogeneic lymphocytes to produce high levels of IFN-γ, TNF-α and IL-17, hiPSCs only induced allogeneic lymphocytes to produce IL-2 and IL-10, and promote IL-10-secreting regulatory T cell (Treg) generation. Our study suggests that the integration-free hiPSCs had low or negligible immunogenicity, which may result from their induction of IL-10-secreting Treg. 相似文献
7.
Nicola Hardwick Lucas Chan Wendy Ingram Ghulam Mufti Farzin Farzaneh 《Cancer immunology, immunotherapy : CII》2010,59(3):379-388
Despite being of the myeloid lineage, acute myeloid leukaemia (AML) blasts are of low immunogenicity, probably because they
lack the costimulatory molecule CD80 and secrete immunosuppressive factors. We have previously shown that in vitro stimulation
of autologous peripheral blood mononuclear cells (PBMCs) with primary AML cells modified to express CD80 and IL-2 promotes
proliferation, secretion of Th1 cytokines and expansion of activated CD8+ T cells. In this study, we show that allogeneic effector cells (from a healthy donor or AML patients) when stimulated with
IL-2/CD80 modified AML blasts were able to induce the lysis of unmodified AML blasts. Effector cells stimulated with IL-2/CD80AML
blasts had higher lytic activity than cells stimulated with AML cells expressing CD80 or IL-2 alone. Similarly, AML patient
PBMCs primed with autologous IL-2/CD80 AML cells had a higher frequency of IFN-γ secreting cells and show cytotoxicity against
autologous, unmodified blasts. Crucially, the response appears to be leukaemia specific, since stimulated patient PBMCs show
higher frequencies of IFN-γ secreting effector cells in response to AML blasts than to remission bone marrow cells from the
same patients. Although studied in a small number of heterogeneous patient samples, the data are encouraging and support the
continuing development of vaccination for poor prognosis AML patients with autologous cells genetically modified to express
IL-2/CD80. 相似文献
8.
The ability of acute lymphoblastic leukemia (ALL) blasts to mediate costimulatory signals during T-lymphocyte activation was investigated in an experimental model in which monoclonal T-cell populations were stimulated with standardized activation signals (anti-CD3 and anti-CD28 monoclonal antibodies; phytohemagglutinin, PHA). Leukemia cells from 12 consecutive ALL patients with high peripheral blood blast counts were studied. Proliferative T-cell responses were detected for a majority of these patients when irradiated leukemia blasts were used as accessory cells during activation. T-cell cytokine release was also observed for most patients when using nonirradiated ALL accessory cells. Low or undetectable cytokine levels were usually observed for CD8+ clones, whereas the CD4+ clones often showed a broad cytokine response with release of interleukin-2 (IL-2), IL-4, IL-10, IL-13 and interferon gamma(IFN-gamma) in the presence of the ALL accessory cells. ALL blasts were also able to function as allostimulatory cells for normal peripheral blood mononuclear responder cells. However, both T-cell proliferation and cytokine release showed a wide variation between ALL patients. The accessory cell function of ALL blasts showed no correlation with the release of immunomodulatory mediators (IL-2, IL-10, IL-15) or the expression of any single adhesion/costimulatory membrane molecule (CD54, CD58, CD80, CD86) by the blasts. We conclude that for a majority of patients, native ALL blasts can mediate costimulatory signals needed for accessory cell-dependent T-cell activation, but differences in costimulatory capacity between ALL patients affects both the proliferative responsiveness and cytokine release by activated T cells. 相似文献
9.
10.
Lymphocyte subpopulations of regional lymph nodes in human colon and gastric adenocarcinomas 总被引:3,自引:0,他引:3
Beatriz Lores-Vazquez Margarita Pacheco-Carracedo Josefina Oliver-Morales Purificación Parada-Gonzalez F. Gambón-Deza 《Cancer immunology, immunotherapy : CII》1996,42(6):339-342
In order to study the host immune response to tumours, previous knowledge of the cellular composition of regional draining
lymph nodes is necessary. Enlarged regional lymph nodes are a common finding in colon and gastric adenocarcinomas. We have
studied the cellular composition of normal non-reactive and of regional draining lymph nodes of colon and gastric adenocarcinomas.
In normal non-reactive lymph nodes, T lymphocytes (CD2+, CD7+) constituted the largest fraction of the lymphoreticular cells. These lymphocytes were mainly CD4+, and there were more cells expressing the CD45RA isoform of the CD45 antigen than CD45RO. Reactive lymph nodes presented
a decreased proportion of CD4+ CD45RA+ cells and an increased number of B cells. Although most of the T cells in the reactive nodes were CD4+ CD45RO+, their proportion was similar to that found in normal non-reactive nodes. We studied the presence of the molecules CD28 and
CD80 involved in the processes of interaction and activation of T and B lymphocytes. The CD28 molecule was found in all the
T lymphocytes, while the CD80 molecule was weakly expressed on the B lymphocyte membrane.
Received: 4 January 1996 / Accepted: 28 May 1996 相似文献
11.
Albrecht J Frey M Teschner D Carbol A Theobald M Herr W Distler E 《Cancer immunology, immunotherapy : CII》2011,60(2):235-248
Clinical tumor remissions after adoptive T-cell therapy are frequently not durable due to limited survival and homing of transfused
tumor-reactive T cells, what can be mainly attributed to the long-term culture necessary for in vitro expansion. Here, we
introduce an approach allowing the reliable in vitro generation of leukemia-reactive cytotoxic T lymphocytes (CTLs) from naive
CD8+ T cells of healthy donors, leading to high cell numbers within a relatively short culture period. The protocol includes the
stimulation of purified CD45RA+ CD8+ T cells with primary acute myeloid leukemia blasts of patient origin in HLA-class I-matched allogeneic mixed lymphocyte-leukemia
cultures. The procedure allowed the isolation of a large diversity of HLA-A/-B/-C-restricted leukemia-reactive CTL clones
and oligoclonal lines. CTLs showed reactivity to either leukemia blasts exclusively, or to leukemia blasts as well as patient-derived
B lymphoblastoid-cell lines (LCLs). In contrast, LCLs of donor origin were not lysed. This reactivity pattern suggested that
CTLs recognized leukemia-associated antigens or hematopoietic minor histocompatibility antigens. Consistent with this hypothesis,
most CTLs did not react with patient-derived fibroblasts. The efficiency of the protocol could be further increased by addition
of interleukin-21 during primary in vitro stimulation. Most importantly, leukemia-reactive CTLs retained the expression of
early T-cell differentiation markers CD27, CD28, CD62L and CD127 for several weeks during culture. The effective in vitro
expansion of leukemia-reactive CD8+ CTLs from naive CD45RA+ precursors of healthy donors can accelerate the molecular definition of candidate leukemia antigens and might be of potential
use for the development of adoptive CTL therapy in leukemia. 相似文献
12.
We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype
(Id)-specific CD8+ cytotoxic T lymphocytes (CTL) are generated in mice following hyperimmunization with irradiated tumor cells, and that they
are effective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor
progression, but are not sustained. At the early stage of tumor growth, the splenic T cells following a 5-day incubation in
vitro with killed 2C3 tumor targets, produce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon γ
(IFNγ). Their cytotoxic T lymphocyte (CTL) activity and cytokine levels, except IL-2, sharply decline at the late stage when
the mice are increasingly moribund. Although the decline in cytokine level is also evident with CD4+ T cells, a precipitous and concurrent decrease occurs primarily in the IL-4 level with both CD4+ and CD8+ T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4
is produced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition
of supernatants from the splenocyte culture of early TBA, or by IL-4, but not by IFNγ and IL-10. In addition, only IL-4-activated
CD8+ T cells from the late TBA are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain
antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising
host immunity against the tumor. We contend that induction or maintenance of protective immunity depends not only on the tumor
antigen but also on the specific cytokine milieu in a tumor-bearing host.
Received: 8 February 1997 / Accepted: 24 April 1997 相似文献
13.
H. Belfrage Mikael Dohlsten Gunnar Hedlund Terje Kalland 《Cancer immunology, immunotherapy : CII》1997,44(2):77-82
Injection of the superantigen staphylococcal enterotoxin A (SEA) activates both CD4+ and CD8+ T cells expressing certain families of T cell receptor (TCR) variable-region β (Vβ) chain. T cells respond with profound cytokine production and induction of cytotoxicity. Repeated injections, however, cause
deletion and anergy of both CD4+ and CD8+ T cells, resulting in reduced frequency of SEA-responsive cells TCR-Vβ11+ as well as reduced cytokine levels in serum upon challenge with SEA. Exogenous interleukin-2 (IL-2) in vivo rescued SEA-responsive
CD4+ and CD8+ cells from SEA-induced deletion and/or increase expansion of SEA-primed cells as well as preventing down-regulation of endogenous
IL-2 production in vivo. Combined treatment with SEA and IL-2 also superinduced production of important cytokines for the
cytotoxic function of T cells, tumour necrosis factor α, interferon γ and IL-6, on a cellular level. These studies show that
continuous stimulation with IL-2 in vivo could be useful for superantigen-based immunotherapy by induction of excessive T
cell activation and by prevention of the development of T cell deletion and anergy.
Received: 29 August 1996 / Accepted: 16 January 1997 相似文献
14.
The dynamics of the expression of the high-affinity receptor for interleukin-2 (IL-2 receptor) evaluated by the method of
flow cytofluorimetry based on changes in the number of cells that express the CD25 marker (CD25+) was studied in human peripheral
blood lymphocytes stimulated by various mitogens. It has been shown that, in the resting lymphocyte culture, both phytohemagglutinin
(PHA, 10 μg/ml) and 12,13-phorbol dibutyrate (PDBu, 10−8 M) with ionomycin (IM, 5 × 10−7 M) induce a long-lasting increase (for 48 h) in the number of CD25+ cells. Interleukin-2 (IL-2) has only been found to be
capable of inducing time-dependent CD25 expression in competent (not resting) lymphocytes pretreated with submitogenic doses
of PHA (1 μg/ml). A comparison of the dynamics of the number of CD25+ cells and blast transformation has shown that CD25 markers
are revealed as early as on small stimulated lymphocytes, while, at the late activation stages, which correspond to the stage
of cell growth and transition to DNA synthesis, the overwhelming majority of blasts are CD25+ cells with high-affinity α -receptors
for IL-2. The obtained data allow one to suggest that the expression of an α -subunit of IL-2 receptor takes place at the
IL-2-dependent stage of T lymphocyte proliferation and may be directly induced by IL-2 via IL-2 receptor. 相似文献
15.
Wendy Ingram Shahram Kordasti Lucas Chan Linda D. Barber Gee J. Tye Nicola Hardwick Ghulam J. Mufti Farzin Farzaneh 《Cancer immunology, immunotherapy : CII》2009,58(10):1679-1690
Immunotherapeutic strategies are increasingly being explored as a method of enhancing anti-tumour immune responses in patients
with acute myeloid leukaemia (AML). Regulatory CD4+ T cells (Tregs) suppress effector T and natural killer (NK) cells and therefore pose a potential challenge to the efficacy
of immunotherapy. AML cells transduced with a lentivirus expressing CD80 (B7.1) and IL2 (LV-CD80/IL2) are capable of stimulating
T and NK cell cytotoxicity in vitro. This study examines the effect of CD80/IL2 modified AML cells on Treg number and function.
We report a significant increase in the number of CD8+ T cells (P = 0.046) CD3−CD56+ NK cells (P = 0.028) and CD3+CD4+CD25highFoxp3+ Tregs (P = 0.043) following stimulation for 7 days with allogeneic LV-CD80/IL2 AMLs. In contrast, autologous LV-CD80/IL2 AML cell
cultures provide a weaker stimulation with a lower number of CD8+ T cells (P = 0.011) and no change in NK cell or Treg numbers. However, an increase in cytotoxic CD8+ T cells and NK cells are detected following both allogeneic and autologous LV-CD80/IL2 stimulation as demonstrated by an
increase in IFN-γ and CD107a expression. Despite the presence of increased numbers of Tregs with suppressive activity in a
subset of cultures, increased lysis of unmodified AMLs was still achieved following allogeneic (day 0, 2.2%; day 7, 20.4%)
and more importantly, autologous LV-CD80/IL2 culture in which AML patients had recently received intensive chemotherapy (day
0, 0%; day 7, 16%). Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune
responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses. 相似文献
16.
Suping Ren Lina Chai Chunyan Wang Changlan Li Qiquan Ren Lihua Yang Fumei Wang Zhixin Qiao Weijing Li Min He Adam I. Riker Ying Han Qun Yu 《PloS one》2015,10(3)
Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow’s 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. 相似文献
17.
Butler MO Imataki O Yamashita Y Tanaka M Ansén S Berezovskaya A Metzler G Milstein MI Mooney MM Murray AP Mano H Nadler LM Hirano N 《PloS one》2012,7(1):e30229
Background
Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model.Methods/Principal Findings
We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells.Conclusions
We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro. 相似文献18.
19.