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1.
Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours 总被引:3,自引:0,他引:3
T. Schöndorf Heike Engel Carsten Lindemann Hannelore Kolhagen Alexander A. von Rücker Peter Mallmann 《Cancer immunology, immunotherapy : CII》1997,44(2):88-96
Immunotherapy of gynaecological cancer with tumour-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) has
become a valid treatment modality with varying degrees of success in obtaining an antitumour response. TIL consist of lymphocytes,
mainly T cells and minor populations of natural killer cells or B cells. Conventional cytogenetic studies of tumour cells
from patients with breast and ovarian cancer have shown multiple chromosomal abnormalities including chromosomes 7 and 12.
This study was designed to analyse the surface further, as well as investigate the intracellular, characteristics of TIL by
multicolour flow cytometry and the cytogenetic features by fluorescence in situ hybridization. Tumour cell, peripheral blood
and TIL samples from 25 patients (15 ovarian tumours, 8 breast cancers, 1 uterine sarcoma, 1 cervical carcinoma) were analysed
for their phenotype, the expression of major cytokines [interleukin-2 (IL-2), IL-4 and interferon γ (IFNγ)], their proliferation
rate, their cytotoxic ability and for the presence of numerical aberrations of chromosomes 7 and 12. All the tumour cells
showed a high frequency of numerical aberration in chromosomes 7 and 12, especially trisomies or tetrasomies and combined
aberrations. Trisomies of both chromosomes also occured at a low percentage in TIL and PBL.
Received: 20 June 1996 / Accepted: 4 January 1997 相似文献
2.
Ursula Elsässer-Beile Ulrich Wetterauer Wolfgang Schultze-Seemann Harald Gallati Jürgen Schulte Mönting Sabine von Kleist 《Cancer immunology, immunotherapy : CII》1996,42(2):93-98
The immunological properties of tumor-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal
cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated
from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all
non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads.
These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1α (IL-1α), IL-1β, IL-2, interferon γ
(IFNγ), and tumor necrosis factor α (TNFα) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures
a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of
each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1α, IL-1β, IFNγ and TNFα were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing
capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.
Received: 8 August 1995 / Accepted: 23 January 1996 相似文献
3.
Diana Risin Eugenie S. Kleinerman Yasuiki Umezu Roland P. Pizzini Charles M. Balch Neal R. Pellis 《Cancer immunology, immunotherapy : CII》1995,40(1):57-64
The ability of the lymphocytes to move through the interstitium is obligatory to the immune response. We previously showed
that tumor-infiltrating lymphocytes (TIL) from human melanoma and renal cell carcinoma demonstrate a dramatic decrease in
their spontaneous locomotion through three-dimensional collagen gel when compared with peripheral blood lymphocytes (PBL)
and lymph node lymphocytes. To determine if this decrease is caused by contact with tumor cells, or mediated through certain
diffusible factors, we examined the effects of autologous tumor cells on the locomotion of PBL in a model system where tumor
cells were separated from lymphocytes by a 3-mm layer of gelled collagen. After 21–22 h incubation in chamber slides, locomotion
distances were assessed in the presence and absence of tumor and normal cells. In the presence of tumor cells, PBL from 14
of 18 patients displayed substantial (466.5 ±2.7 μm compared to control 568.9 ± 10.9 μm, P<0.001) loss of motility. Inhibition was more prominent in melanoma patients than in renal cell carcinoma patients. Thus the
impaired locomotion previously observed in TIL was at least partially due to the presence of tumor. The locomotion of TIL
was restored in four of five melanoma patients treated with liposome-encapsulated muramyl-tripeptide-phosphatidylethanolamine
(L-MTP-PE). Furthermore, in six of seven examined L-MTP-PE-treated patients, an increase in intrinsic PBL locomotion during
the first month of the therapy was observed. These results suggest that the environment of the tumor is not conducive to locomotion
of advancing lymphocytes and the therapeutic intervention may ameliorate the loss of lymphocytic infiltration.
Received: 16 May 1994 / Accepted: 26 August 1994 相似文献
4.
M. K. Gjersten Ingvil Sæterdal Klaus Beiske Gustav Gaudernack 《Cancer immunology, immunotherapy : CII》1997,43(5):262-268
Mesothelial cells obtained from ascites fluid of a Ras-peptide vaccinated pancreatic adenocarcinoma patient were cultured
in vitro. Fresh isolated cells expressed HLA class II molecules, which were lost upon culture, but could be up-regulated after
coculture with human recombinant interferon-γ. The antigen-presenting capacity of these mesothelial cells was tested with
allogeneic peripheral blood mononuclear cells (PBMC) in a mixed lymphocyte mesothelial cell culture and by stimulating autologous
PBMC with purified protein derivative of Mycobacterium tuberculosis. Cloned T cells from the same patient allowed us to test the ability of mesothelial cells to present a mutant Ras-derived
peptide to specific T cells in a DLA-DR-restricted manner. Mesothelial cells effectively stimulated allogeneic resting T lymphocytes
to proliferate and presented soluble protein antigen or a mutant Ras-derived peptide to specific T cells, indicating that
they display processing and presenting capabilities. Since mesothelial cells are in close anatomical relationship with intraabdominal
malignancies, they may contribute to stimulation of specific T cells by endocytosing tumour-specific antigens and presenting
them to T lymphocytes. This could be a possible mechanism in which mesothelial cells participate in maintaining local specific
immunity in patients already primed.
Received: 17 July 1996 / Accepted: 15 October 1996 相似文献
5.
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
6.
A. P. M. van der Meijden P. A. Steerenberg I. M. W. van Hoogstraaten J. A. Kerckhaert L. M. H. Schreinemachers E. J. Harthoorn-Lasthuizen A. M. Hagenaars W. H. de Jong F. M. J. Debrujine E. J. Ruitenberg 《Cancer immunology, immunotherapy : CII》1989,28(4):287-295
Summary The immune reactivity of patients with strongly recurrent superficial bladder cancer was followed after combined intravesical and intradermal bacillus Calmette-Guérin (BCG) immunotherapy. All patients in this study were previously treated without success with intravesical chemotherapy. The BCG treatment regimen consisted of weekly administrations with BCG (RIVM) for six consecutive weeks, both intravesically and intradermally. In this study, sera and peripheral blood leukocytes (PBL) of patients were tested serially. Besides BCG-antigen-specific reactions, e.g. skin reactivity to purified protein derivatives of Mycobacterium tuberculosis (PPD), antibody formation and antigen stimulation of PBL in vitro, non-antigen-specific immune reactivities were also measured, e.g. mitogen response and spontaneous cytotoxic activity of PBL. In addition the antibody response to bladder carcinoma antigens and the cytotoxic activity of PBL for the bladder carcinoma cell line T24 and the natural-killer-sensitive K562 cell line were investigated. The results obtained from the various assays were evaluated for their prognostic value in relation to the length of the tumor-free interval after the BCG treatment. Because sera and PBL were only obtained during the first 6 months after the BCG treatment, the immune reactivity was compared to the clinical results at that same time. At 6 months after therapy 12 out of 40 BCG-treated patients were tumor-free whereas 28 out of 40 showed a recurrence. Skin reactivity to tuberculin PPD was measured in 40 patients during a period of 3–6 months after therapy. Of patients who showed a recurrence of the tumor within 6 months, 48% of them showed a transient response or developed no response at all to PPD. In the group of patients with a longer tumor-free period (n=10), only one patient lost the response to tuberculin PPD. Although PBL of a limited number of patients were tested, it was observed that the cytotoxicity to the bladder carcinoma cell line T24, and the natural-killer-sensitive K562 cell line increased in a number of the patients (7 out of 14, and 9 out of 14 respectively). Reactivity of PBL to mitogens and subset distribution (ratio T-helper: T-suppressor/cytotoxic) were not influenced by the BCG treatment. Antibody response to mycobacterial antigen was detected in 9 out of 23 patients investigated. Of these 9 patients, 8 belonged to the group with a recurrence of the tumor within 6 months (n=17). There was no correlation between the skin reactivity and the antibody response to tuberculin PPD. Furthermore, none of the 25 patients showed an antibody response to bladder carcinoma antigens. Sera of bladder carcinoma patients (n=19) reduced the mitogen-induced proliferation of lymphocytes, compared to sera of healthy controls (n=13), indicating the presence of circulating suppressor factor(s). Our results indicate that the absence of a Mantoux conversion or the presence of transient reaction to tuberculin PPD were highly related (91%) to a relapse of the disease. On the other hand, the cytotoxic activity of PBL to T24 and K562 cell lines, or their reactivity to tuberculin PPD or mitogens, gives no predictive information about the clinical results (tumor-free interval) of the BCG therapy.
Abbreviations used: BCG, bacillus Calmette-Guérin; NK, natural killer; PBL, peripheral blood leukocytes; PPD, purified protein derivative of Mycobacterium tuberculosis; ELISA, enzyme-linked immunosorbent assay 相似文献
7.
Inhibition of rat C6 glioblastoma tumor growth by expression of insulin-like growth factor I receptor antisense mRNA 总被引:3,自引:0,他引:3
Mariana Resnicoff Weiping Li Saroj Basak Dorothee Herlyn Renato Baserga R. Rubin 《Cancer immunology, immunotherapy : CII》1996,42(1):64-68
The expression of insulin-like growth factor I receptor (IGF-IR) antisense mRNA inhibits the growth of C6 rat glioblastoma
cells both in vitro and in vivo [Cancer Res (1994) 54: 2218]. Moreover, the injection of C6 cells expressing an antisense
mRNA to the IGF-IR into syngeneic rats prevents subsequent wild-type tumorigenesis and induces regression of established tumors.
For the study of immune function in syngeneic rats, C6 cells expressing either IGF-IR sense or IGF-IR antisense mRNA were
injected and splenic lymphocyte function analyzed in vitro after 2 weeks. Cytotoxic, CD8+ lymphocytes from animals injected with IGF-IR antisense cells, but not from those treated with IGF-IR sense cells, proliferated
in vitro in response to wild-type C6 cells. Wild-type C6 cells or IGF-IR-sense-RNA-expressing cells rapidly formed tumors
upon subcutaneous injection into athymic nude mice. IGF-IR antisense cells were weakly tumorigenic, exhibiting a six- to tenfold
increase in tumor latency. Injection of IGF-IR antisense C6 cells mildly delayed the development of wild-type tumors, and
did not induce the regression of established wild-type C6 tumors in athymic nude mice. Thus, these findings demonstrate the
stimulation of a cellular immune response in rats following the injection of IGF-IR antisense cells. However, studies of athymic
nude mice indicate that expression of IGF-IR antisense mRNA also inhibits C6 cells tumorigenicity by additional mechanisms.
Received: 27 January 1995 / Accepted: 15 November 1995 相似文献
8.
John A. Johnkoski Steven M. Peterson R. J. Doerr S. A. Cohen 《Cancer immunology, immunotherapy : CII》1997,43(5):299-306
We have previously shown that levamisole increases the cytotoxic, cytostatic, and proliferative activity of murine nonparenchymal
liver cells (NPC) in vitro. We have also shown that the nonadherent subpopulation of NPC, which are composed predominantly
of T lymphocytes, is very responsive to this agent when administered to mice. Kupffer cells or immigrant macrophages are also
responsive to levamisole but to a lesser extent. These findings prompted us to investigate changes in cytokine production
by NPC following-treatment of mice with levamisole (25 mg/kg, i.p.), which may help explain the observed alterations in the
immune functions of these cells. We found that levamisole treatment of mice causes a threefold increase in production of interferon
(IFN) α/β by adherent NPC (more than 80% – 90% Kupffer cells) in vitro. When IFN α/β was added to cultured cells, it decreased
the proliferative capacity of liver T cells in a dose-dependent manner. In contrast, the addition of anti-IFNα/β was shown
to augment levamisole-induced proliferation of unfractionated NPC and Kupffer cells. NPC production of interleukin 1 (IL-1)
and interleukin-6 (IL-6) in vitro was also increased threefold following treatment of mice with levamisole. IL-6 added in
vitro to cells significantly augmented levamisole-induced proliferation of liver T cells while anti-IL-6 reduced proliferative
activity to control levels. These findings suggested that IFNα/β, IL-6, and IL-1 play important regulatory roles in controlling
the proliferative response of murine liver-associated T lymphocytes to levamisole. Finally, the proliferation of bone marrow
cells was increased in mice given 5-fluorouracil (5FU). On the other hand, the proliferation of NPC was dramatically suppressed
when 5FU was administered. However, the proliferation of these cells was restored when levamisole was given after 5FU.
Received: 27 November 1995 / Accepted: 16 October 1996 相似文献
9.
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
10.
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
11.
Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献
12.
N. Jacobs Roland Greimers Alessandra Mazzoni Mohamed Trebak Nicole Schaaf-Lafontaine Jacques Boniver Michel P. Moutschen 《Cancer immunology, immunotherapy : CII》1996,42(6):369-375
In this study we have specifically investigated the participation of T cells in the cytotoxic activity of peripheral blood
lymphocytes (PBL) activated by interleukin-2 (IL-2, 50 U/ml) alone or in combination with an anti-CD3 mAb (BMA030, 10 ng/ml,
IgG2a). Purified CD3+ T cells, incubated in the presence of the anti-CD3 mAb for 4 days, mediated a cytotoxic activity against HL60 and U937 tumor
cell lines. Several findings suggested the involvement of a redirected-cytotoxicity phenomenon, since the lytic process was
restricted to target cell lines bearing the high-affinity Fcγ receptor (FcγRI) and T lymphocytes stimulated by IL-2 alone
did not lyse these cell lines. Furthermore, anti-CD3 mAb F(ab′)2, anti-CD3 IgG1 (UCHT1), phytohemagglutinin or staphylococcal enterotoxin A did not induce a similar cytotoxic activity in
T lymphocytes. The cytotoxic process occurred in the presence of a very low level of anti-CD3 antibodies (in the nanomolar
range). The cytotoxic activity of T cells stimulated by IL-2 or by IL-2 + BMA030, against OVCAR-3 cells (MOv18+ ovarian tumor cell line), was also compared in the presence of a bispecific antibody (OC/TR, anti-CD3 × MOv18). The stimulation
by IL-2 + BMA030 induced approximately a twofold higher cytotoxic activity than IL-2-activated T cells. This could be related
to the state of activation of effector cells stimulated by IL-2 + BMA030, since the phenotypic analysis showed an increased
proportion of T cells expressing several activation/differentiation markers (CD25, HLA-DR, CD45R0, adhesion molecules). These
findings could be applied to the design of therapeutic protocols using anti-CD3 ×antitumoral bispecific antibodies.
Received: 6 December 1995 / Accepted: 4 June 1996 相似文献
13.
Tomoe Higuchi Masumi Shimizu Atsuko Owaki Megumi Takahashi Eiji Shinya Taiji Nishimura Hidemi Takahashi 《Cancer immunology, immunotherapy : CII》2009,58(8):1245-1255
Intravesical bacillus Calmette-Guerin (BCG) therapy is considered the most successful immunotherapy against solid tumors of
human bladder carcinoma. To determine the actual effector cells activated by intravesical BCG therapy to inhibit the growth
of bladder carcinoma, T24 human bladder tumor cells, expressing very low levels of class I MHC, were co-cultured with allogeneic
peripheral blood mononuclear cells (PBMCs) with live BCG. The proliferation of T24 cells was markedly inhibited when BCG-infected
dendritic cells (DCs) were added to the culture although the addition of either BCG or uninfected DCs alone did not result
in any inhibition. The inhibitory effect was much stronger when the DCs were infected with live BCG rather than with heat-inactivated
BCG. The live BCG-infected DCs secreted TNF-α and IL-12 within a day and this secretion continued for at least a week, while
the heat-inactivated BCG-infected DCs secreted no IL-12 and little TNF-α. Such secretion of cytokines may activate innate
alert cells, and indeed NKT cells expressing IL-12 receptors apparently proliferated and were activated to produce cytocidal
perforin among the PBMCs when live BCG-infected DCs were externally added. Moreover, depletion of γδ T-cells from PBMCs significantly
reduced the cytotoxic effect on T24 cells, while depletion of CD8β cells did not affect T24 cell growth. Furthermore, the
innate effectors seem to recognize MICA/MICB molecules on T24 via NKG2D receptors. These findings suggest the involvement
of innate alert cells activated by the live BCG-infected DCs to inhibit the growth of bladder carcinoma and provide a possible
mechanism of intravesical BCG therapy. 相似文献
14.
S. Lausson B. Fournes C. Borrel G. Milhaud F. Treilhou-Lahille 《Cancer immunology, immunotherapy : CII》1996,43(2):116-123
The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC), and their resistance to all classical therapies,
make it a prime candidate for adoptive immunotherapy. As a prelude to a vaccine for the protection of family members at risk
of developing the disease, we investigated the immunological antitumour response provoked by the 6/23 rMTC cell line, compared
to that of the same cells engineered to secrete interleukin-2 (rMTC-IL2), in an animal model of familial human MTC, the inbred
strain of Wag/Rij rats. The rMTC cells developed a tumour that invaded the whole neck 15 days after orthotopic injection (into
the thyroid), while the rMTC-IL2 cells were progressively rejected. Co-injection of rMTC-IL2 with the parental cells induced
the rejection of the rMTC transplants. When injected, both tumoral cell types showed a similar positive immunoreaction with
anti-MHC class I (major histocompatibility complex class I) antibodies. They both recruited natural killer cells and eosinophils
at the site of injection. In addition, CD8+ T lymphocytes infiltrated the rMTC-IL2 cells, and eosinophil recruitment was amplified. Neutrophils, macrophages and CD4+ T lymphocytes were scarce. Our results suggest that the CD8+ T lymphocytes are implicated in the antitumour reaction elicited by the Il-2-transfected cells. As these effectors are known
to induce a specific immunological response, including memory, such a protocol should be tested as a vaccine on the young
population genetically at risk of developing a MTC.
Received: 18 December 1995 / Accepted: 21 August 1996 相似文献
15.
Fataki Bombil Jean Pierre Kints Xavier Havaux Jean Marie Scheiff Hervé Bazin Dominique Latinne 《Cancer immunology, immunotherapy : CII》1995,40(6):383-389
The transfer of human peripheral blood mononuclear cells (hu-PBMC) from adult Epstein-Barr- virus(EBV)-seropositive donors
in SCID (severe combined immunodeficiency) mice frequently leads to the development of a human B lymphoproliferative syndrome
(hu-BLPS). Therefore, as 90% of adult potential donors are EBV-seropositive, efforts have to be made to avoid the occurrence
of this B lymphoproliferative disorder. McCune et al. [Science 241:1632 (1988)] used human fetal organs for a human SCID graft.
This system does not give rise to hu-BLPS but human fetal organs are much less available than peripheral blood leucocytes.
The experiments reported in this paper show how crucial is the presence of functional T lymphocytes for a graft to take and for development of hu-BLPS in hu-PBMC-reconstituted SCID mice, since inhibition of
T lymphocyte by a rat anti-(human CD2) monoclonal antibody (LO-CD2a) during the first 10 days of the graft prevents successful
engraftment of human normal lymphocytes as well as hu-BLPS in SCID mice. The transfer of B cells alone or B cells plus monocytes
in SCID mice does not permit either long-term engraftment or development of hu-BLPS. We also demonstrate that hu-PBMC treated
with L-leucine methyl ester are less susceptible to the development of hu-BLPS after engraftment in SCID mice than are untreated
hu-PBMC. The mechanism of action of L-leucine methyl ester on these cells is discussed.
Received: 12 December 1994 / Accepted: 20 March 1995 相似文献
16.
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
17.
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
18.
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
19.
β-Fructofuranosidase was purified from commercial alkaline protease (Aspergillus oryzae origin). The optimal pH of its transfructosylating activity was more alkaline (pH 8) than that of its hydrolyzing activity
(pH 5). In the case of a 24-h reaction with sucrose, the hydrolysis and transfructosylation reaction were optimal at pH 4–5
and pH 8, respectively. In the reaction at pH 8 1-kestose and nystose were the main fructooligosaccharides produced. The transfer
ratio was hardly different between pH 5 and pH 8 early in the reaction, but the transfer products (1-kestose and nystose)
were decreased at pH 5 as the reaction proceeded because of their hydrolysis.
Received: 18 January 1995/Received last revision: 23 August 1995/Accepted: 13 September 1995 相似文献
20.
Toshihiro Fujimoto Michael A. O’Donnell Akos Szilvasi H. Yang R. B. Duda 《Cancer immunology, immunotherapy : CII》1996,42(5):280-284
Although immunotherapy with bacillus Calmette Guérin (BCG) is an established adjuvant treatment for malignant melanoma, the
mechanism of its role in this process is unclear. To investigate the possible contribution of tumor-inhibitory cytokines induced
by BCG, B16F10 melanoma cell growth in culture was assessed in response to purified cytokines and conditioned media of BCG-stimulated
splenocytes. Interferon-γ (IFNγ) was the most potent single agent (IC50≈50 pg/ml). Tumor necrosis factor α was substantially weaker (IC50>10 ng/ml) but provided synergy with IFNγ. None of the other
cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, or granulocyte/macrophage-colony-stimulating factor had
direct antitumor activity against B16F10 melanoma cells. However, when IL-2 and/or GM-CSF were combined with BCG either by
exogenous addition or through endogenous production by novel cytokine-secreting recombinant BCG (rBCG), a substantial increase
in INFγ production by splenocytes was observed. Antitumor activity of this conditioned medium directly correlated with IFNγ
concentration and was completely blocked by neutralizing antibody to IFNγ. These results suggest that BCG may exert part of
its antitumor action on melanoma through the induction of IFNγ, which can be greatly enhanced through the concomitant addition
of IL-2 and/or GM-CSF. Furthermore, by utilizing rBCG that secrete these cytokines, it may be possible to potentiate the antitumor
effect of BCG directly at the site of BCG inoculation.
Received: 29 January 1996 / Accepted: 9 April 1996 相似文献