共查询到20条相似文献,搜索用时 15 毫秒
1.
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
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.
Lola Weiss Samir Nusair Shoshana Reich Haim Sidi S. Slavin 《Cancer immunology, immunotherapy : CII》1996,43(2):103-108
The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone
marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/lymphoma. Allogeneic cell therapy,
induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic
activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing
mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes
with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained
from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic
lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved
after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can
be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by
allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal
residual disease provided that graft versus host disease can be prevented or adequately controlled.
Received: 14 May 1996 / Accepted: 6 August 1996 相似文献
4.
F. Vánky Noémi Nagy Christina Hising Kerstin Sjövall Eva Klein 《Cancer immunology, immunotherapy : CII》1997,43(6):317-323
We tested 20 human carcinoma samples for the production of transforming growth factor β (TGFβ) in vitro. Tumour cell suspensions
without obvious contamination with non-malignant cells were kept in culture conditions for 16 h and their supernatants were
added to CCL-64 cells. The proliferation of these cells is inhibited by TGFβ. According to this assay, the supernatants contained
both active and latent TGFβ. In addition, the supernatants were found to suppress the spontaneous cytotoxic function and activation
of T-cell-enriched lymphocyte populations. A specific monoclonal antibody (mAb) counteracted these effects and therefore we
concluded that they were mediated to a large extent by TGFβ. In line with the results obtained with the supernatants, activation
of lymphocytes could also be inhibited by tumour cells and their inhibitory effect was weaker in the presence of the TGFβ-specific
mAb. It is important to note that, when TGFβ-specific mAb was added to autologous mixed lymphocyte/tumour cell cultures, lymphocyte
activation occurred more often. These results thus substantiate the assumption that production of TGFβ may help the survival
of potentially immunogenic tumour cells in immunocompetent patients.
Received: 21 August 1996 / Accepted: 12 November 1996 相似文献
5.
Keith R. Jerome Allan D. Kirk Gabriele Pecher Wayne W. Ferguson O. J. Finn 《Cancer immunology, immunotherapy : CII》1997,43(6):355-360
The human mucin, MUC-1, is a transmembrane glycoprotein that is produced by both normal an malignant epithelium. The MUC-1
produced by malignant epithelium is underglycosylated, which leads to the expression by tumors of novel T and B cell epitopes
on the mucin polypeptide core. Similar underglycosylation occurs in the lactating breast. In this report, we describe a long-term
survivor of breast cancer whose tumor strongly expressed the T- and B-cell-stimulatory epitopes. Five years after presenting
with the tumor, the patient had her first pregnancy, at which time she developed fulminant lymphocytic mastitis. We demonstrate
that the lactating breast produced mucin expressing the same “tumor-specific” epitopes as the original cancer. The patient
had circulating anti-mucin antibodies of both the IgM and IgG isotypes (these are not found in normal controls), and mucin-specific
cytotoxic T lymphocytes in the peripheral blood. Limiting – dilution analysis for mucin – specific cytotoxic T lymphocytes
in three different experiments yielded frequencies of 1 in 3086, 1 in 673, and 1 in 583, compared to approximately 1 in 106 in normal controls. The patient remains clinically free of carcinoma after 5 additional years of follow-up. We propose that
the original tumor primed the patient’s immune response against the mucin epitopes, and that the re-expression of these epitopes
on the lactating breast evoked a secondary immune response. It is tempting to speculate that the vigor of her anti-mucin immunity
may have helped protect this patient against recurrent tumor.
Received: 12 February 1996 / Accepted: 5 November 1996 相似文献
6.
Labarrière N Gervois N Bonnin A Bouquié R Jotereau F Lang F 《Cancer immunology, immunotherapy : CII》2008,57(2):185-195
Choosing a reliable source of tumor-specific T lymphocytes and an efficient method to isolate these cells still remains a
critical issue in adoptive cellular therapy (ACT). In this study, we assessed the capacity of MHC/peptide based immunomagnetic
sorting followed by polyclonal T cell expansion to derive pure polyclonal and tumor-reactive Melan-A specific T cell populations
from melanoma patient’s PBMC and TIL. We first demonstrated that this approach was extremely efficient and reproducible. We
then used this procedure to compare PBMC and TIL-derived cells from three melanoma patients in terms of avidity for Melan-A
A27L analog, Melan-A26–35 and Melan-A27–35, tumor reactivity (lysis and cytokine production) and repertoire. Regardless of their origin, i.e., fresh PBMC, peptide stimulated
PBMC or TIL, all sorted populations (from the three patients) were cytotoxic against HLA-A2+ melanoma cell lines expressing
Melan-A. Although some variability in peptide avidity, lytic activity and cytokine production was observed between populations
of different origins in a given patient, it differed from one patient to another and thus no correlation could be drawn between
T cell source and reactivity. Analysis of Vβ usage within the sorted populations showed the recurrence of Vβ3 and Vβ14 subfamilies
in the three patients but differences in the rest of the Melan-A repertoire. In addition, in two patients, we observed major
repertoire differences between populations sorted from the three sources. We especially documented that in vitro peptide stimulation
of PBMC, used to facilitate the sort by enriching in specific T lymphocytes, could significantly alter their repertoire and
reactivity towards tumor cells. We conclude that PBMC which are easily obtained from all melanoma patients, can be as good
a source as TIL to derive high amounts of tumor-reactive Melan-A specific T cells, with this selection/amplification procedure.
However, the conditions of peptide stimulation should be improved to prevent a possible loss of reactive clonotypes.
Nathalie Labarrière and Nadine Gervois have equally contributed to this work. 相似文献
7.
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
8.
Takami Sato 《Cancer immunology, immunotherapy : CII》1996,43(3):174-179
We have developed a novel approach to cancer immunotherapy – an autologous whole-cell vaccine modified with the hapten dinitrophenyl
(DNP). This approach elicits significant inflammatory responses in metastatic sites and some objective tumor responses. Post-surgical
adjuvant immunotherapy with DNP-modified melanoma vaccine in a setting of micrometastatic disease produces significant survival
prolongation in stage III melanoma patients. Histologically, the inflammatory responses of the tumor consist of infiltration
by lymphocytes, the majority of which are CD8+, HLA-DR+ T cells. T cells from these lesions tend to have mRNA for interferon γ. T cell receptor analysis suggests that the tumor-infiltrating
T cells are clonally expanded. DNP-modified vaccine also induces T cells in the peripheral blood, which respond to DNP-modified
autologous cells in a hapten-specific, MHC-restricted manner. Moreover, a T cell line generated from these lymphocytes responded
to only a single HPLC fraction of MHC-associated, DNP-modified tumor peptides. Since inflammatory responses in metastases
were not consistently associated with dramatic tumor regression, we considered the possibility of immunosuppression at the
tumor site. We found that mRNA for the anti-inflammatory cytokine, interleukin-10 (IL-10) is expressed in most metastatic
melanoma tissues and subsequently demonstrated that IL-10 protein is produced by melanoma cells. Thus the efficacy of DNP
vaccine could be further enhanced by inhibition of IL-10 production or binding. Finally, we expect these results obtained
with melanoma to be applicable to other human cancers.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
9.
Cellular immune responses to autologous chronic myelogenous leukaemia cells in vitro 总被引:2,自引:0,他引:2
Graham Pawelec Arnika Rehbein Elke Schlotz Paul da Silva 《Cancer immunology, immunotherapy : CII》1996,42(3):193-199
Using a modification of the autologous mixed lymphocyte/tumour cell culture (MLTC), it is demonstrated here that lymphocytes
from chronic-phase myelogenous leukaemia (CML) patients (n = 58), but not from their HLA-identical siblings, proliferated upon coculture with autologous tumour cells. However, in most
cases, the level of proliferation measured was low (stimulation index <3, n = 37). This was most likely related to the amount of interleukin-10 (IL-10) released into the culture medium by the CML cells,
because addition of neutralizing anti-IL-10 serum to MLTC markedly enhanced proliferative responses. In addition, supplementation
of media with IL-1α further enhanced proliferative responses and a combination of anti-IL-10 serum and IL-1α was more effective
than either agent alone. Only HLA-DR-matched CML cells, but not HLA-DR-mismatched CML cells or matched or mismatched PBMC
restimulated proliferation of IL-2-dependent T cell lines derived from MLTC supplemented with IL-1α and anti-IL-10 serum.
The responding cells under these conditions were predominantly CD4+ and secreted IL-2, and interferon γ; some secreted IL-4, but none secreted IL-10. These data therefore suggest the existence
of an HLA-DR-restricted DTH/Th1-type of tumour-specific immunity in CML patients, which may be down-regulated in vitro by
excessive secretion of IL-10 together with depressed secretion of IL-1.
Received: 9 November 1995 / Accepted: 8 February 1996 相似文献
10.
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
11.
K. A. O. Ellem Michael G. E. O’Rourke Gregory R. Johnson Gordon Parry Ihor S. Misko Christopher W. Schmidt Peter G. Parsons Scott R. Burrows Simone Cross Andrew Fell Chung-Leung Li John R. Bell Philip J. Dubois Denis J. Moss Michael F. Good Anne Kelso Lawrence K. Cohen Glenn Dranoff Richard C. Mulligan 《Cancer immunology, immunotherapy : CII》1997,44(1):10-20
The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells
as a therapeutic vaccine in a patient with rapidly progressive, widely disseminated malignant melanoma resulted in the generation
of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction
to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing
magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH
sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the
histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma
cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture
without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein
was observed, as was a systemic eosinophilia. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation
of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system
metastases; however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune
response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted
in rapid deterioration and death of the patient.
Received: 20 September 1996 / Accepted: 5 December 1996 相似文献
12.
Kiley Prilliman Mark Lindsey Y. Zuo Ken W. Jackson Ying Zhang W. Hildebrand 《Immunogenetics》1997,45(6):379-385
A peptide-based vaccine must be bound and presented by major histocompatibility complex class I molecules to elicit a CD8+ T-cell response. Because class I HLA molecules are highly polymorphic, it has yet to be established how well a vaccine peptide
that stimulates one individual’s CD8+ cytotoxic T lymphocytes will be presented by a second individual’s different class I molecules. Therefore, to facilitate
precise comparisons of class I peptide binding overlaps, we uniquely combined hollow-fiber bioreactors and mass spectrometry
to assign precise peptide binding signatures to individual class I HLA molecules. In applying this strategy to HLA-B*1501, we isolated milligram quantities of B*1501-bound peptides and mapped them using mass spectrometry. Repeated analyses consistently assign the same peptide binding
signature to B*1501; the degree of peptide binding overlap between any two class I molecules can thus be determined through comparison of
their peptide signatures.
Received: 3 October 1996 / Revised: 20 November 1996 相似文献
13.
The adoptive transfer of immune T cells is capable of mediating the regression of established neoplasms in a variety of animal
tumor models. The antitumor activity is invariably proportional to the number of cells transferred, thus methods to expand
immune cell number while maintaining therapeutic efficacy have been extensively investigated. Here we demonstrate that a short-term
culture of immune T cells can amplify the T cell number and enhance the therapeutic reactivity against established pulmonary
tumor, while maintaining immunological specificity. In contrast, the therapeutic reactivity of immune T cells against established
subcutaneous tumor is diminished by short-term culture. While cultured immune T cells are not cytotoxic in a 4-h Cr-release
assay, they do specifically secrete interferon γ upon stimulation with tumor cells. T cells cultured after a single exposure
to tumor are even more active against pulmonary tumor than T cells cultured from mice immunized repeatedly. This culture system
can rapidly induce T cell proliferation and differentiation into mature effector cells, and the resulting cells demonstrate
an enhanced ability to treat visceral metastases, but a decreased ability to treat subcutaneous tumor. Thus T cells cultured
after a single exposure to tumor represent an ideal population of cells for use in human adoptive immunotherapy trials.
Received: 18 July 1996 / Accepted: 27 September 1996 相似文献
14.
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
15.
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
16.
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
17.
Chungwen Wei Eugene Storozynsky A. J. McAdam Kun-Yun Yeh Brian R. Tilton Richard A. Willis Richard K. Barth R. John Looney Edith M. Lord J. G. Frelinger 《Cancer immunology, immunotherapy : CII》1996,42(6):362-368
Human prostate-specific antigen (PSA) has a highly restricted tissue distribution. Its expression is essentially limited
to the epithelial cells of the prostate gland. Moreover, it continues to be synthesized by prostate carcinoma cells. This
makes PSA an attractive candidate for use as a target antigen in the immunotherapy of prostate cancer. As a first step in
characterizing the specific immune response to PSA and its potential use as a tumor-rejection antigen, we have incorporated
PSA into a well-established mouse tumor model. Line 1, a mouse lung carcinoma, and P815, a mouse mastocytoma, have been transfected
with the cDNA for human PSA. Immunization with a PSA-expressing tumor cell line demonstrated a memory response to PSA which
protected against subsequent challenge with PSA-expressing, but not wild-type, tumors. Tumor-infiltrating lymphocytes could
be isolated from PSA-expressing tumors grown in naive hosts and were specifically cytotoxic against a syngeneic cell line
that expressed PSA. Immunization with tumor cells resulted in the generation of primary and memory cytotoxic T lymphocytes
(CTL) specific for PSA. The isolation of PSA-specific CTL clones from immunized animals further demonstrated that PSA can
serve as a target antigen for antitumor CTL. The immunogenicity studies carried out in this mouse tumor model provide a rationale
for the design of methods to elicit PSA-specific cell-mediated immunity in humans.
Received: 4 April 1996 / Accepted: 31 May 1996 相似文献
18.
P. Pellegrini Anna Maria Berghella T. Del Beato Sergio Cicia Domenico Adorno Carlo Umberto Casciani 《Cancer immunology, immunotherapy : CII》1996,42(1):1-8
Recent theories have established that, during an ongoing immune response, the lymphokines produced by TH1 and TH2 subsets
of CD4+ T cells are critical to the effectiveness of that response. In vivo and in vitro studies have demonstrated that the type
of environmental cytokines plays a determinant role in directing the development of naive T cells into TH1 or TH2 effector
cells. Disregulated expansion of one or other subset may contribute to the development of certain diseases. To establish whether
a similar situation might exist in the cells of the peripheral blood (PBMC) of colorectal cancer patients, we have performed
immunological studies on a group of patients and a group of healthy subjects. We examined the interleukin-2 (IL-2), interferon
γ (IFNγ), IL-4, IL-6 and tumour necrosis factor α levels in serum; the production of IL-4 and IL-2, with and without activating
agents, by PBMC, tumour-draining lymph node lymphocytes and tumour cells; and the proliferative response of PBMC to IL-2,
IL-4 and anti-CD3 monoclonal antibody (anti-CD3), which were variously combined. The data of the present study lead us to
hypothesize that, because of suppressive effects probably due to environmental IL-4, in the peripheral blood of patients there
seems to be a disregulation in the functionality of TH1 and TH2 subsets of CD4+ T cells, with an expansion in TH2 and a malfunction in TH1 cells. Moreover it seems that this disregulation increases with
as the disease progresses through the stages, suggesting that it can be directly implicated in the mechanisms that allow the
tumour to locate and progress in the host.
Received: 27 June 1995 / Accepted: 13 November 1995 相似文献
19.
Sonja Fischer Armin Scheffler D. Kabelitz 《Cancer immunology, immunotherapy : CII》1997,44(3):150-156
Mistletoe (Viscum album) extracts are widely used in adjuvant cancer therapy. We have investigated the in vitro responsiveness of T cells from mistletoe-treated
cancer patients and untreated healthy donors to various preparations of mistletoe extracts. Proliferation of peripheral blood
mononuclear cells from treated but not from untreated patients was observed in response to therapeutically used mistletoe
extracts prepared from apple (mali) or pine (pini) host trees. The strongest proliferation was induced by a vesicle preparation of mali extract. Activation was strongly inhibited by interleukin-10. Using a newly developed flow-cytometry assay, we determined
that cell growth was restricted to CD4 T cells. Analysis with a panel of monoclonal antibodies against the variable region
of the T cell receptor β chain (Vβ) revealed an oligoclonal pattern of CD4 T cell activation. These results indicate that
therapeutic administration of mistletoe extracts sensitizes a restricted set of CD4 T lymphocytes in mistletoe-treated patients.
Received: 25 May 1996 / Accepted: 9 January 1997 相似文献
20.
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