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1.
Induction of antitumor immunity after cure of pulmonary metastases, using staphylococcal enterotoxin B and bispecific antibody 总被引:1,自引:0,他引:1
David C. Rice Andrei I. Chapoval Louis Porter Heidi Nelson 《Cancer immunology, immunotherapy : CII》1999,48(5):230-238
The combination of staphylococcal enterotoxin B (SEB) and anti-p97 x anti-CD3 bispecific antibody (bsAb) cures 60%-80% of mice with established pulmonary metastases of the syngeneic p97+ murine melanoma, CL62. We investigated the ability of cured mice to generate protective antitumor immunity. In tumor rechallenge experiments, CL62-cured mice developed protective immunity against rechallenge with CL62. The majority of mice also rejected the p97-negative parental cell line, K1735, indicating an immune response to tumor antigens common to both cell lines that were not bsAb-targeted. A significant humoral response developed against p97 antigen, but not against other antigens common to both CL62 and K1735. That the majority of cured mice nevertheless rejected K1735 suggests that tumor immunity is not antibody-dependent. Evidence of cellular immunity was obtained from the results of delayed-type hypersensitivity, proliferation and cytotoxicity assays, which revealed the presence of tumor-specific memory in bsAb-treated, CL62-cured mice. CD8+ T cells from cured, but not control mice were able to lyse tumor; however, memory CD4 cells had no cytolytic function. In vivo, however, both CD4 and CD8 T cells were required for effective protective immunity. These studies demonstrate that treatment with SEB and bsAb not only confers passive immune effects of tumor eradication, but also actively promotes the generation of a host antitumor immune response. 相似文献
2.
3.
Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies 总被引:4,自引:0,他引:4
A new type of cancer vaccine for therapeutic application in cancer patients is described. It consists of three components.
(1) autologous tumor cells, (2) Newcastle Disease Virus (NDV), to be used for infection and (3) bispecific antibodies (bsAb)
which attach to the viral hemagglutinin neuraminidase (HN) molecule on the infected tumor cells. A standardized procedure
has been developed for generating virus infected human autologous tumor cell vaccines (ATV-NDV) which includes cell dissociation,
removal of leukocytes and cell debris, gamma-irradiation and cryopreservation. Infection with the non-virulent strain NDV
Ulster is performed within 30 min of co-incubation. While virus infection already increased immunogenicity of the tumor vaccine,
further augmentation of T cell stimulatory capacity is achieved by attachment of specially designed bi-specific antibodies
(bs HN × CD28 or bs HN × CD3).
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
4.
Ingmar A. F. M. Heijnen Martin J. Glennie J. G. J. van de Winkel 《Cancer immunology, immunotherapy : CII》1997,45(3-4):166-170
The class I IgG receptor (FcγRI) on cytotoxic effector cells has been reported to initiate destruction of tumour cells by
effector cells in vitro. We are aiming at developing an immunocompetent model to evaluate the cytotoxic capacity of human
FcγRI for the rejection of tumour cells in vivo. Therefore, we recently generated a transgenic mouse strain expressing human
FcγRI on monocytes, macrophages, and neutrophils. In these mice, the human receptor is up-regulated by granulocyte-colony-stimulating
factor (G-CSF) and is able to trigger cellular responses. Subsequently, in the present study the B cell lymphoma IIA1.6 cell
line is selected as a tumour target, and a human FcγRI-directed antitumour bispecific antibody (bsAb) is constructed and characterized.
Fab′ fragments of mAb 22, which bind hFcγRI at an epitope that is distinct from the ligand binding site, were chemically linked
to Fab′ fragments of rat anti-(mMHC class II antigens) mAb M5/114, yielding bsAb 22×M5/114. This bsAb was able to bind simultaneously
to hFcγRI and mMHC class II antigens in a dose-dependent fashion. Binding of 22×M5/114 to FcγRI was not inhibited in the presence
of human IgG. It is important to note that, MHC-class-II-expressing IIA1.6 lymphoma cells were lysed by whole blood from G-CSF-treated
transgenic mice in the presence of bsAb 22×M5/114. No lysis by whole blood from non-transgenic mice or from transgenic animals
that had not received G-CSF was observed. These results indicate that human FcγRI is able to mediate lysis of murine IIA1.6
lymphoma cells by transgenic effector cells via bsAb 22×M5/114. A trial with transgenic mice, evaluating the efficacy of these
hFcγRI-directed bsAb in combination with G-CSF for treatment of IIA1.6 B cell lymphoma, is currently in progress.
Accepted: 14 October 1997 相似文献
5.
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
6.
T. D. Nguyen Melanie J. Smith Peter Hersey 《Cancer immunology, immunotherapy : CII》1997,43(6):345-354
Determinants of T cell responses to tumor cells remain largely unknown. In the present study we have used long-term cultures
of human melanoma cells and autologous peripheral blood lymphocytes to examine the influence of cytokines with T cell growth
activity on the phenotype and cytotoxic and proliferative response of T cells to melanoma. It was found that addition of interleukin-4
(IL-4) inhibited the response of CD8+ T cells and promoted the response of the CD4 subset. IL-2 or IL-7 was effective in increasing melanoma-specific cytotoxic
T lymphocyte (CTL) activity in cultures where CD8 T cells were predominant, whereas IL-4 followed by IL-2 was most effective
in cultures where CD4 T cells predominated. IL-10 or IL-12 inhibited proliferation and CTL activity against melanoma in long-term
cultures. The effects of IL-12 were reproduced in long-term cultures of T cells stimulated with mAb against CD3 and were shown
to depend on prior exposure of T cells to IL-12 before IL-2. As yet unidentified factors, such as co-factor expression on
melanoma, appear to be as important as exogenous cytokines in determining the nature of T cell responses to melanoma. These
results suggest that analysis of responses in long-term culture may assist in defining the role of key cytokines and other
determinants of immune responses to melanoma.
Received: 4 June 1996 / Accepted: 12 November 1996 相似文献
7.
Ex vivo activation of tumor-draining lymph node T cells reverses defects in signal transduction molecules 总被引:2,自引:0,他引:2
J. Liu James Finke John C. Krauss Suyu Shu G. E. Plautz 《Cancer immunology, immunotherapy : CII》1998,46(5):268-276
The adoptive transfer of tumor-draining lymph node (LN) T cells activated ex vivo with anti-CD3 and interleukin 2 (IL-2)
mediates the regression of the poorly immunogenic murine melanoma D5. The efficacy of the activated LN cells is augmented
when the sensitizing tumor is a genetically modified variant (designated D5G6) that secretes granulocyte/macrophage-colony-stimulating
factor. In contrast to anti-CD3/IL-2-activated LN cells, adoptive transfer of freshly isolated tumor-draining LN T cells has
no therapeutic activity. To determine whether the acquisition of antitumor function during ex vivo activation is associated
with modifications in signal transduction capacity, the protein tyrosine kinases p56
lck
and p59
fyn
and proteins of the NF-κB family were analyzed in tumor-draining LN T cells. The levels of p56
lck
and p59
fyn
were lower in tumor-draining than in normal LN T cells and production of tyrosine-phosphorylated substrates was markedly
depressed following anti-CD3 stimulation. After 5-day anti-CD3/IL-2 activation, levels of p56
lck
and p59
fyn
and protein tyrosine kinase activity increased. Interestingly, the levels of p56
lck
, p59
fyn
, and tyrosine kinase activity were higher in activated T cells derived from LN that drained D5G6 than they were in those
from D5 tumors. In contrast, the cytoplasmic levels of c-Rel and Rel A were normal in freshly isolated tumor-draining LN,
as was nuclear κB DNA-binding activity induced by anti-CD3 mAb or phorbol myristate acetate. Stimulation of activated LN cells
with D5 tumor cells induced the nuclear translocation of NF-κB. These findings indicate that the recovery of proteins mediating
signal transduction through the T cell receptor/CD3 complex in LN T cells activated ex vivo was associated with the acquisition
of antitumor function.
Received: 28 August 1997 / Accepted: 23 February 1998 相似文献
8.
Nathalie Jacobs Alessandra Mazzoni Delia Mezzanzanica Donatella R. M. Negri Olga Valota Maria I. Colnaghi Michel P. Moutschen Jacques Boniver Silvana Canevari 《Cancer immunology, immunotherapy : CII》1997,44(5):257-264
T cell triggering can be achieved by monoclonal antibodies (mAbs) specific for the CD3/TcR complex. In the presence of appropriate
costimulation and/or progression factors, such triggering permits the generation of effector cells for immunotherapy protocols
involving the redirection of T cell lysis against tumor cells by mAbs bispecific for anti-CD3/anti-tumor cells (bs-mAbs).
Focusing our analysis on the clinically relevant bs-mAb OC/TR, we found that bs-mAbs generated with the same anti tumor specificity,
but two other anti-CD3 mAbs, TR66 and OKT3, have the same and a significantly lower lytic potential, respectively, compared
with that of OC/TR. To evaluate the relevance of the anti-CD3 component, we examined several anti-CD3 mAbs with respect to
binding parameters and the ability to trigger T lymphocytes. Competitive binding assays suggested that all anti-CD3 mAbs recognized
the same or overlapping epitopes, although mAbs BMA030 and OC/TR bound with lower avidity than did αCD3 (the bivalent anti-CD3
mAb produced by the hybrid hybridoma OC/TR), TR66 and OKT3, as determined by measurement of the affinity constants. In all
lymphocyte populations examined, which included resting peripheral blood mononuclear cells (PBMC), activated PBMC and T cell
clones, OKT3, BMA033 and OC/TR failed to mobilize Ca2+ without cross-linking, whereas αCD3, in both murine and murine-human chimeric versions, TR66 and BMA030, did not require
cross-linking. The ability to induce CD3 modulation was associated in part with the induction of Ca2+ fluxes. Despite the differences in the behavior of these mAbs in triggering the events that precede proliferation, all of
them ultimately led to expression of the IL-2 receptor and to proliferation in T cells in the presence of accessory cells.
Our data suggest that anti-CD3 mAbs that bind more rapidly (strong Ca2+ mobilizers) and more tightly under physiological conditions are good candidates for retargeting T cells in the bs-mAb clinical
application.
Received: 2 January 1997 / Accepted: 6 February 1997 相似文献
9.
W. M. C. Mulder M. J. Stukart E. de Windt J. Wagstaff R. J. Scheper E. Bloemena 《Cancer immunology, immunotherapy : CII》1996,42(6):351-356
Mucins (MUC) are highly glycosylated molecules widely expressed on epithelia of different origins, including colonic mucosa.
Altered glycosylation processes in tumour cells result in the exposure of normally cryptic peptide epitopes, which may then
be recognized as tumour-specific antigens. Recently, MUC1-specific antibodies were detected in the serum of a broad range
of cancer patients, and from different tumours tumour-specific cytotoxic T lymphocytes (CTL) were isolated that recognized
MUC1. Absence of HLA restriction in the recognition has been ascribed to the highly repetitive sequence of the polypeptide
core, allowing simultaneous recognition of multiple identical epitopes and cross-linking and aggregation of T cell receptor
on mucin-specific T cells. We investigated the expression of MUC1 epitopes in 56 cell suspensions from Dukes’ B to D colorectal
carcinomas using antibodies that recognize distinct peptide sequences on the glycosylated or deglycosylated MUC1 protein backbone.
No relation was observed between MUC1 expression, or the extent of its glycosylation, and Dukes’ stage, tumour location and
tumour differentiation, but a positive correlation was detected between the percentages of tumour cells expressing mucin-1
and the numbers of CD3+ infiltrating cells. These tumour-infiltrating lymphocytes contained, however, only a few MUC1-specific T lymphocytes, as
CTL showing preferential killing of MUC1-expressing target cells were only obtained from one tumour. Since, in addition, the
majority of colorectal carcinomas were found to express the fully glycosylated MUC1 glycoprotein, its potential role as a
target antigen for T-lymphocyte-mediated immunotherapy in this tumour type is probably limited.
Received: 2 April 1996 / Accepted: 28 May 1996 相似文献
10.
11.
12.
Wei-Dong Yu Ming-Jei Chang Donald L. Trump C. S. Johnson 《Cancer immunology, immunotherapy : CII》1997,44(6):316-322
Interleukin-1α (IL-1α) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated
antitumor responses. Studies were undertaken to examine the ability of IL-1α to enhance the activity of cyclophosphamide (CTX)
administered in combination with carboplatin. To determine the in vivo effect of IL-1α, CTX and/or carboplatin, mice bearing
14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5–150 mg/kg), human IL-1α
(125 μg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell
assay. Even at the lowest doses of CTX, IL-1α significantly enhanced the clonogenic tumor cell kill when compared to treatment
with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor
regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1α or CTX/carboplatin). Significant
enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1α. The interaction between the three-drug
combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for
IL-1α and CTX when used in this combination. These results demonstrate that IL-1α can synergistically enhance the antitumor
efficacy of CTX and the combination of CTX and carboplatin.
Received: 11 September 1996 / Accepted: 20 May 1997 相似文献
13.
Jamie Honeychurch Andrew Cruise Alison L. Tutt M. J. Glennie 《Cancer immunology, immunotherapy : CII》1997,45(3-4):171-173
Despite the success of mAb and bispecific (bs)Ab in the treatment of certain malignancies, there is still considerable uncertainty
about the most appropriate format in which they should be used. In the current work we have investigated a panel of bsAb [IgG
and F(ab)2] with dual specificity for T cells and neoplastic B cells. Throughout this work, anti-CD2 or anti-CD3 were used to bind the
mouse T cells, and antibodies to surface IgM idiotype (Id), CD19, CD22, or MHC class II were used to target mouse B cell lymphomas
BCL1 or A31. In vitro, killing was measured in a conventional cytotoxicity assay using 51Cr-labelled A31 and BCL1 cells as targets and activated mouse splenocytes as effectors. bsAb showed a wide range of cytotoxic activities, which could
be ranked in the following order: [anti-CD3×anti-class-II]>[anti-CD3×anti-CD19] >[anti-CD3×anti-Id]>[anti-CD3×anti-CD22],
with the [anti-CD2×anti-Id] derivative showing relatively little cytotoxic activity. This hierarchy of activity indicates
some correlation with the binding activity of the bsAb on target cells, but showed a much stronger parallel with the tendency
of the anti-(target cells) mAb to undergo antigenic modulation (less modulation, more killing). In vivo, the situation was
completely different and only the anti-ld derivatives, [anti-CD3×anti-ld] and [anti-CD2×anti-ld], were effective in prolonging
the survival of tumour-bearing animals. Under optimal conditions Id-positive tumour was eradicated with a single treatment
of bsAb. We conclude from this work that the target cell specificity of a bsAb is critical in determining therapeutic outcome
and that in vitro cytotoxicity assays do not predict in vivo activity.
Accepted: 14 October 1997 相似文献
14.
Taxol-mediated changes in fibrosarcoma-induced immune cell function: Modulation of antitumor activities 总被引:6,自引:0,他引:6
David W. Mullins Thomas M. Walker Carol J. Burger Klaus D. Elgert 《Cancer immunology, immunotherapy : CII》1997,45(1):20-28
The anticancer drug taxol (paclitaxel) inhibits tumors through multiple cytotoxic and cytostatic mechanisms. Independently
of these mechanisms, taxol induces distinct immunological efficacy when it acts as a second signal for activation of tumoricidal
activity by interferon-γ(IFNγ)-primed murine normal host macrophages. We reported that tumor-distal macrophages, which mediate
immunosuppression through dysregulated nitric oxide (NO) and tumor necrosis factor α (TNFα) production, are differentially
regulated by taxol. Because taxol influences tumor cell growth dynamics and activates immune cell populations, we assessed
the ex vivo immunosuppressive and antitumor activities of taxol-treated normal host and tumor-bearing host (TBH) macrophages.
Pretreatment of such cells with taxol partly reconstituted T cell alloantigen reactivity, suggesting that taxol mediates a
limited reversal of TBH macrophage immunosuppressive activity. Taxol-treated TBH macrophages significantly suppressed the
growth of fibrosarcoma cells (Meth-KDE) through soluble effector molecules and promoted direct cell-mediated cytotoxicity,
indicating that taxol enhanced tumor-induced macrophage antitumor activities. Tumor-induced helper T cells, however, showed
a higher sensitivity to direct taxol-induced suppression. These data demonstrate that taxol exerts pleiotropic effects on
antitumor immune responses with the capacity to abate the immunosuppressive activities of macrophages and promote macrophage-mediated
antitumor activities simultaneously, but also directly modulating T cell reactivity. Collectively, these studies suggest that
the antineoplastic drug taxol may impart antitumor activity through an immunotherapeutic capacity.
Received: 31 December 1996 / Accepted: 1 July 1997 相似文献
15.
Heike K. E. Boxhorn Jason G. Smith Yueh J. Chang DuPont Guerry William M. F. Lee Ulrich Rodeck Laurence A. Turka Stephen L. Eck 《Cancer immunology, immunotherapy : CII》1998,46(5):283-292
Previous studies in experimental models have demonstrated that the transduction of human or murine melanoma cells with the
co-stimulatory B7-1 molecule induces effective antitumor immune responses. In order to develop B7-1 gene transfer as a therapeutic
tool in the clinical management of melanoma, efficient means of in vivo gene transfer must be used. To this end we evaluated
in vitro and in vivo immune responses associated with adenoviral transduction of murine and human melanoma cells with B7-1.
Adenovirus-mediated transduction of human and murine melanoma cells with B7-1 leads to high-level transgene expression in
vitro and in vivo and does not affect MHC class I and II expression. Adenovirus-delivered B7-1 induced antitumor immune responses,
on the basis of observations that human melanoma cells transduced to express human B7-1 were able to co-stimulate allogeneic
and autologous T cells to proliferate and that murine melanoma K1735 cells transduced to express murine B7-1 were rejected
by syngeneic, immunocompetent mice. By contrast, intratumoral injection of an adenovirus encoding murine B7-1 failed to eliminate
established murine melanoma (K1735) despite high-level transgene expression in tumor cells. Potent T cell inhibitory factor(s)
secreted by both K1735 cells and select human melanoma cells may contribute to the failure to achieve protection in this setting.
Thus, immune inhibitory melanoma-derived factors need to be taken into account when considering the clinical use of B7-1 immunotherapy.
Received: 21 December 1997 / Accepted: 16 March 1998 相似文献
16.
Brandl C Haas C d'Argouges S Fisch T Kufer P Brischwein K Prang N Bargou R Suzich J Baeuerle PA Hofmeister R 《Cancer immunology, immunotherapy : CII》2007,56(10):1551-1563
BiTE molecules comprise a new class of bispecific single-chain antibodies redirecting previously unstimulated CD8+ and CD4+ T cells for the elimination of target cells. One example is MT103 (MEDI-538; bscCD19xCD3), a CD19-specific BiTE that can induce lysis of normal and malignant B cells at low picomolar concentrations, which is accompanied by T cell activation. Here, we explored in cell culture the impact of the glucocorticoid derivative dexamethasone on various activation parameters of human T cells in response to MT103. In case cytokine-related side effects should occur with BiTE molecules and other T cell-based approaches during cancer therapy it is important to understand whether glucocorticoids do interfere with the cytotoxic potential of T cells. We found that MT103 induced in the presence of target cells secretion by peripheral T cells of interleukin (IL)-2, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, IL-10 and IL-4 into the cell culture medium. Production of all studied cytokines was effectively reduced by dexamethasone at a concentration between 1 and 3x10(-7) M. In contrast, upregulation of activation markers CD69, CD25, CD2 and LFA-1 on both CD4+ and CD8+ T cells, and T cell proliferation were barely affected by the steroid hormone analogue. Most importantly, dexamethasone did not detectably inhibit the cytotoxic activity of MT103-activated T cells against a human B lymphoma line as investigated with lymphocytes from 12 human donors. Glucocorticoids thus qualify as a potential co-medication for therapeutic BiTE molecules and other cytotoxic T cell therapies for treatment of cancer. 相似文献
17.
Efficient induction of antitumor cytoxic T lymphocytes from a healthy donor using HLA-A2-restricted MAGE-3 peptide in vitro 总被引:1,自引:0,他引:1
F. Tanaka Tatsuo Fujie Hiroki Go Kinya Baba Masaki Mori Kazutoh Takesako Tsuyoshi Akiyoshi 《Cancer immunology, immunotherapy : CII》1997,44(1):21-26
The antigenic peptides encoded by tumor-rejection antigen genes, MAGE-1 and -3, have been identified, and various methods have been utilized for the in vitro induction of MAGE-specific, cytotoxic
T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) using synthetic peptides. However, all of these methods
are technically demanding and thus have a relatively limited usefulness. We herein report a simple and efficient method for
the in vitro induction of specific CTL by using the HLA-A2-restricted MAGE-3 peptide from the PBMC of a healthy donor. CTL
responses could thus be efficiently induced from unseparated PBMC by stimulation with freshly isolated, peptide-pulsed PBMC
as antigen-presenting cells and by using interleukin-7 and keyhole limpet hemocyanin for the primary culture. The induced
CTL could thus recognize and lyse not only HLA-A2 target cells pulsed with the peptide but also HLA-A2 tumor cells expressing
MAGE-3, in an HLA-class-I-restricted manner. This simple method may, therefore, become a useful tool for investigating the
potential peptides for tumor antigens as well as for developing various immunotherapeutic approaches for human malignant tumors.
Received: 15 October 1996 / Accepted: 6 December 1996 相似文献
18.
C. Renner Gerhard Held Sascha Ohnesorge Stefan Bauer Klaus Gerlach Jan-Peter Pfitzenmeier Michael Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,44(2):70-76
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes,
induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis
contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation,
FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for
perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity
in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative
state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance
of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells
in bi-mAb-mediated apoptosis and necrosis of tumor cells.
Received: 5 December 1996 / Accepted: 16 January 1997 相似文献
19.
G. Raes J. Van Ginderachter Yuan Qing Liu L. Brys Kristiaan Thielemans Patrick De Baetselier Anja Geldhof 《Cancer immunology, immunotherapy : CII》1997,45(5):257-265
BW-Sp3 is a BW-5147-derived T cell lymphoma with limited immunogenicity since, despite regression of the majority of subcutaneous
tumors, an important fraction of the animals will die from metastases. In the present study, the BW-Sp3 cells were transfected
with genes encoding B7-1 or B7-2, known to be involved in the induction of T cell responses. The resulting transfectants exhibited
a reduced tumorigenicity and did not cause mortality in the syngeneic recipients. Furthermore, immunization with the B7-1
or B7-2 transfectants resulted in an increased generation of cytotoxic T lymphocytes (CTL) that lysed both the transfectants
and the wild-type BW-Sp3 cells. Since the B7 transfectants were completely rejected in syngeneic recipients and induced potent
CTL recognizing the wild-type BW-Sp3 cells, these engineered cells were considered as candidates for immunotherapy. Vaccinations
with the B7-1 or B7-2 transfectants could completely protect the animals from metastatic disease when subsequently challenged
with wild-type BW-Sp3 cells. Furthermore, immunization with the B7 transfectants could prolong the survival time of mice that
had been challenged intravenously with BW-Sp3 cells. Surprisingly, however, when these transfectants, as well as the wild-type
BW-Sp3 cells, were used for vaccination of tumor-bearing animals, the presence of the subcutaneous BW-Sp3 tumors clearly interfered
with the outcome of immunotherapy, resulting in increased malignancy, as reflected by a higher incidence of progressing tumors
and a reduced survival rate. Possible implications for immunotherapy in humans are discussed.
Received: 5 August 1997 / Accepted: 15 August 1997 相似文献
20.
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