共查询到20条相似文献,搜索用时 15 毫秒
1.
Ursula Holzer Wolfgang Bethge Frauke Krull Johannes Ihle Rupert Handgretinger Ralph A. Reisfeld Mikael Dohlsten Terje Kalland Dietrich Niethammer Günther E. Dannecker 《Cancer immunology, immunotherapy : CII》1995,41(2):129-136
Superantigens such as the staphylococcal enterotoxin A (SEA) are among the most potent T cell activators known. They bind
to major histocompatibility complex (MHC) class II molecules and interact with T cells depending on their T cell receptor
(TCR) Vβ expression. Superantigens also induce a variety of cytokines and trigger a direct cytotoxic effect against MHC-class-II-positive
target cells. In order to extend superantigen-dependent cell-mediated cytotoxicity (SDCC) to MHC-class-II-negative neuroblastoma
cells, SEA was linked to the anti-ganglioside GD2 human/mouse chimeric monoclonal antibody (mAb) ch14.18. Ganglioside GD2 is expressed on most tumours of neuroectodermal origin but is expressed to a lesser extent on normal tissues. The linkage
of ch14.18 to SEA was achieved either with a protein-A–SEA fusion protein or by chemical coupling. Both constructs induced
T-cell-mediated cytotoxicity towards GD2-positive neuroblastoma cells in an effector-to-target(E:T)-ratio-and dose-dependent manner in vitro. To reduce the MHC class
II affinity of SEA, a point mutation was introduced in the SEA gene (SEAm9) that resulted in 1000-fold less T cell killing
of MHC-class-II-expressing cells as compared to native SEA. However, a protein-A–SEAm9 fusion protein mediated cytotoxicity
similar to that of protein-A–SEA on ch14.18-coated, MHC-class-II-negative neuroblastoma cells. Taken together, these findings
suggest that superantigen-dependent and monoclonal-antibody-targeted lysis may be a potent novel approach for neuroblastoma
therapy.
Received: 15 March 1995 / Accepted: 22 May 1995 相似文献
2.
Ayako Enomoto Kazunori Kato Hideo Yagita K. Okumura 《Cancer immunology, immunotherapy : CII》1997,44(4):204-210
In this study, we examined the therapeutic antitumor effect of cytotoxic T lymphocytes (CTL) generated against CD86-transfected
mouse neuroblastoma C1300. We first generated the transfectant, CD86+C1300, expressing a high level of mouse CD86 on the cell surface. While CD86+C1300 cells were rejected in syngeneic A/J mice when inoculated subcutaneously, neither vaccination nor any therapeutic antitumor
effect was obtained, implying that C1300 may be a poorly immunogenic tumor. However, in vitro stimulation of splenocytes from
either C1300-bearing or CD86+C1300-rejecting mice with CD86+C1300 cells resulted in remarkable CTL activity against C1300 cells. The CTL activity induced by CD86+C1300 was mediated by T cell receptor/CD3 and CD8 and was further enhanced by the addition of interleukin-2. Intravenous inoculation
of C1300 cells led to multiple organ metastases including the liver, lung, kidney, ovary, lymph node and bone marrow. To examine
the therapeutic effect of CTL in this metastasis model, CTL induced by parental or CD86+C1300 cells were administrated into C1300-bearing mice. Adoptive transfer of CD86+C1300-induced CTL resulted in marked elimination of multi-organ metastases and prolonged survival in almost all mice, 70%
of which survived indefinitely. These results indicate that adoptive transfer of CTL induced by CD86-transfected tumor cells
in vitro would be effective and useful for tumor immunotherapy against poorly immunogenic tumors.
Received: 18 November 1996 / Accepted: 3 March 1997 相似文献
3.
Induction of accessory cell function of human alveolar macrophages by inhalation of human natural interleukin-2 总被引:1,自引:0,他引:1
Gernot Zissel Walter E. Aulitzky J. Lorenz Christoph Huber J. Müller-Quernheim 《Cancer immunology, immunotherapy : CII》1996,42(2):122-126
Accessory function allows antigen-presenting cells to produce sufficient secondary signals for optimum T cell proliferation
and interleukin-2 (IL-2) production. Alveolar macrophages are inferior accessory cells compared to monocytes (PBM). We report
here that the accessory index (AI) of alveolar macrophages and PBM of patients with lung metastases of solid tumors treated
with inhalations of human natural IL-2 (hnIL-2) increased following its administration (P<0.005). The accessory index was significantly elevated from baseline values after 2 weeks of inhalation of 300 000 IU hnIL-2/day
(8.2±10.2 compared to 1.1±1; P<0.001). The inhalation of 150 000 IU also induced increases in the index (AI = 2.3±1.9), however, without reaching statistical
significance. In addition at 300 000 IU IL-2/day a significant increase in the accessory index was observed for PBM (4±2.5;
P<0.05). The indices of PBM and alveolar macrophages prior to inhalation showed a significant negative correlation with the
age of the patients (r
s = – 0.5; r
s = – 0.8, respectively; P<0.03 for all comparisons). Our data demonstrate that the inhalational application of hnIL-2 enhances the accessory function
of alveolar macrophages and, to lesser extent, the accessory index of PBM, indicating the occurrence of pharmacological immunostimulation.
Received: 16 August 1995 / Accepted: 4 January 1996 相似文献
4.
H. Belfrage Mikael Dohlsten Gunnar Hedlund Terje Kalland 《Cancer immunology, immunotherapy : CII》1997,44(2):77-82
Injection of the superantigen staphylococcal enterotoxin A (SEA) activates both CD4+ and CD8+ T cells expressing certain families of T cell receptor (TCR) variable-region β (Vβ) chain. T cells respond with profound cytokine production and induction of cytotoxicity. Repeated injections, however, cause
deletion and anergy of both CD4+ and CD8+ T cells, resulting in reduced frequency of SEA-responsive cells TCR-Vβ11+ as well as reduced cytokine levels in serum upon challenge with SEA. Exogenous interleukin-2 (IL-2) in vivo rescued SEA-responsive
CD4+ and CD8+ cells from SEA-induced deletion and/or increase expansion of SEA-primed cells as well as preventing down-regulation of endogenous
IL-2 production in vivo. Combined treatment with SEA and IL-2 also superinduced production of important cytokines for the
cytotoxic function of T cells, tumour necrosis factor α, interferon γ and IL-6, on a cellular level. These studies show that
continuous stimulation with IL-2 in vivo could be useful for superantigen-based immunotherapy by induction of excessive T
cell activation and by prevention of the development of T cell deletion and anergy.
Received: 29 August 1996 / Accepted: 16 January 1997 相似文献
5.
Neeta Soni N. J. Meropol Michelle Porter Michael A. Caligiuri 《Cancer immunology, immunotherapy : CII》1996,43(1):59-62
Interleukin-2 (IL-2) is a potent immunomodulator that has been associated with the clinical development of autoimmune disorders.
However, diabetes mellitus has not been reported in patients treated with single-agent IL-2. We conducted a clinical trial
of a protracted daily schedule of subcutaneously administered low-dose IL-2. A patient with advanced colorectal cancer, treated
with 1.5×106 international units of IL-2 daily, developed insulin-requiring diabetes during therapy. Hyperglycemia improved during treatment
interruption and recurred with reinstitution of IL-2. The diabetes in this patient developed in the context of T cell and
natural killer cell expansion, and the presence of islet cell autoantibodies was documented. We postulate that, in this patient,
IL-2 reversed the anergy of autoreactive T cells that had escaped clonal deletion. It is possible that prolonged daily exposure
to immunomodulatory doses of IL-2 will result in the development of autoimmune phenomena not observed with other schedules
of administration.
Received: 15 April 1996 / Accepted: 1 August 1996 相似文献
6.
A. B. Lentsch Koji Nakagawa Hiroyuki Yoshidome Alexandra Gerassimides Frederick N. Miller Michael J. Edwards 《Cancer immunology, immunotherapy : CII》1997,43(6):331-336
The biological activity of all recombinant forms of interleukin-2 (IL-2) is based upon an in vitro lymphocyte proliferation
assay and measured in international units (IU). Numerous in vitro investigations have suggested that there may be different
cellular effects of recombinant human IL-2 retaining the natural sequence (nIL-2) as compared to another recombinant form
containing a serine substitution at amino acid position 125 ([Ser]IL-2). In the present study we investigated whether nIL-2
and [Ser]IL-2 cause similar patterns of systemic toxicities. C57BL/6 mice were treated with identical doses of either nIL-2
or [Ser]IL-2, as measured in IU, for 3 days and had blood and tissues removed for analysis of lymphocyte activation and organ
dysfunction. The administration of nIL-2 had considerably greater effects on lymphocyte activation than did [Ser]IL-2, causing
much greater up-regulation of the α subunit of the IL-2 receptor and the adhesion molecule lymphocyte function-associated
antigen-1. Furthermore, nIL-2 induced more organ edema than did [Ser]IL-2 and caused hepatocellular injury, which was absent
in mice treated with [Ser]IL-2. These data demonstrate that equivalent doses, measured in IU, of nIL-2 and [Ser]IL-2 have
profoundly different effects on the induction of organ toxicity, suggesting that the IU standard may not be appropriate for
the measurement of many in vivo biological activities.
Received: 30 August 1996 / Accepted: 8 November 1996 相似文献
7.
Linda A. Everse Monique R. Bernsen Hub F. J. Dullens Willem Den Otter 《Cancer immunology, immunotherapy : CII》1997,44(4):221-229
We have studied the effect of active specific immunization (ASI) on the antitumor response induced by locoregional, low-dose
interleukin-2 (IL-2) therapy. On day 0, mice were injected i.p. with viable, syngeneic tumor cells and with irradiated tumor
cells (ASI). Low-dose IL-2 treatment was given i.p. for 5 consecutive days. ASI led to extended survival in two out of seven
models tested. In these two models, enhanced efficacy was observed when both ASI and IL-2 were administered. In the five models
in which ASI had no therapeutic value, ASI+IL-2 treatment was no more effective than IL-2 therapy. In the SL2 lymphoma model,
use of ASI prior to IL-2 therapy given as early as days 1–5 led to at least 60% cure, whereas IL-2 therapy without ASI was
only effective when administered after day 9. In the P815 mastocytoma model, however, ASI, IL-2, and the combination caused
negative (suppressive) effects when administered on days 6–10. IL-2 administered on days 6–10 was therapeutically effective
in this model when mice were treated with cyclophosphamide on day 6. In both the SL2 and the P815 tumor models, cured mice
were specifically immune. The positive and negative effects observed were not due to the increased number of cells injected
(non-specific inflammation) nor to possible antigenic alteration of the ASI cells by irradiation, as ASI with fragmented tumor
cells was also effective in inducing synergy. Investigations into the underlying mechanism indicated that CD4+ cells play an important role. In total, the results indicate that ASI may be a good supplement to locoregional IL-2 treatment
if care is taken to alleviate immunosuppressive activities.
Received: 6 February 1997 / Accepted: 6 March 1997 相似文献
8.
Y. Asano K. Kaneda J. Hiragushi T. Tsuchida K. Higashino 《Cancer immunology, immunotherapy : CII》1997,45(2):63-70
A high-dose bolus regimen for interleukin(IL)-2 administration to cancer patients frequently causes serious side-effects
in which various organs are involved. In order to reveal the mechanism of toxicities associated with this regimen, we compared
the augmenting effect of high-dose IL-2 on murine organ-associated lymphocytes between neoplastic and non-neoplastic states.
Intraperitoneal administration of IL-2 at a dose of 105 JRU (Japanese Reference Units) twice daily for 3 days led to the death of all the syngeneic MH134-hepatoma- or X5563-myeloma-bearing
mice, whereas it had no lethal effect on non-tumor-bearing mice. Histological and morphometric analyses demonstrated that
tumor-bearing mice displayed more extensive infiltration of large granular lymphocytes and agranular lymphocytes in the liver
and lungs than did the non-tumor-bearing mice. Large granular lymphocytes had the ultrastructural characteristics of lymphokine-activated
killer cells. Lymphocytes often underwent extravasation into the interstitial space and exhibited local proliferation without
causing any direct injury to apposed parenchymal cells. Flow-cytometric analysis of hepatic mononuclear cells demonstrated
that IL-2-receptor-β(IL-2Rβ)-bearing lymphocytes, i.e., natural killer cells and intermediate CD3 cells, were increased in
number in the neoplastic state before the IL-2 injection. The present study indicates that the tumor-bearing state increases
the number of organ-associated IL-2Rβ+ lymphocytes, which are then greatly amplified by the challenge of high-dose IL-2, leading to the functional disturbance of
organs. We have further demonstrated here that an intermittent low-dose IL-2 regimen has a potential therapeutic effect on
tumor regression without causing lethal side-effects.
Received: 15 July 1996 / Accepted: 23 July 1997 相似文献
9.
Specific anti-EL4-lymphoma immunity in mice cured 2 years earlier with doxorubicin and interleukin-2
M. J. Ehrke Srdan Verstovšek Gintaras Zaleskis Richard L. X. Ho Peter Ujházy Darbie L. Maccubbin Enrico Mihich 《Cancer immunology, immunotherapy : CII》1996,42(4):221-230
This laboratory has reported the conditions for an effective, non-toxic, chemoimmunotherapy utilizing doxorubicin in combination
with prolonged administration of interleukin-2 and the identification of the critical role of activated CD8+ T cells in the therapeutic effect. Mice (C57BL/6) cured in those studies have been followed for the remainder of their life
spans. These mice, approximately 2 months of age when initially inoculated with syngeneic EL4 lymphoma, survived for more
than 2 years, the normal life span of C57BL/6 mice. Mice 4 months old reinoculated with the EL4 cells all survived. At about
1 year of age mice were sacrificed and the ability of their thymocytes and splenocytes to develop specific CD8+ anti-EL4 activity was as high as it had been at the time of tumor rejection. At about 2 years of age EL4 was reimplanted
into mice; all of them survived. These surviving mice, at 2 years 2 months of age, as well as a group of 2-year-old mice not
rechallenged, were killed and functional antitumor activity and phenotype characteristics of various lymphocyte populations
were determined in comparison to those of young and age-matched control mice. The phenotyping of the lymphocytes from the
cured mice indicated very notable differences in subset distribution and increased CD44 expression. Functionally they developed
high levels of anti-EL4 activity, which was ablated by combined treatment with monoclonal antibodies against CD8 and CD44,
indicating the role of memory cells. Consistent with cells from aged mice, these same cell populations had a very reduced
allogeneic responsiveness. It appears that cured mice have developed an immune memory specific for EL4.
Received: 30 November 1995 / Accepted: 20 March 1996 相似文献
10.
L. Yuan Yasuhiro Kuramitsu Yongqin Li Masanobu Kobayashi M. Hosokawa 《Cancer immunology, immunotherapy : CII》1996,41(6):355-362
We studied mechanisms of immunosuppression caused by tumor-derived transforming growth factor-β (TGFβ) and restoration of
the immune response by treatment with bleomycin in rats bearing KDH-8 hepatoma. Interleukin-2 (IL-2) production from splenocytes
of KDH-8-tumor-bearing rats progressively decreased as the KDH-8 tumor grew. IL-2 production from concanavalin-A-stimulated
normal rat splenocytes was signficiantly inhibited by in vitro cultured KDH-8-tumor-cell-conditioned medium; this inhibition
could be blocked by neutralizing the conditioned medium with anti-TGFβ antibody. TGFβ activities were found in KDH-8-tumor-tissue-conditioned
medium without acid treatment and were found in tumor-cell-conditioned medium after acid treatment; TGFβ mRNA and TGFβ protein
were found in cultured KDH-8 tumor cells. These results suggested that the KDH-8-tumor-derived TGFβ might be involved in the
inhibition of IL-2 production from splenocytes. To determine whether bleomycin chemotherapy could reduce tumor-derived TGFβ
and restore the immune responses, we treated KDH-8 tumor-bearing rats with bleomycin (5 mg/kg, one shot) at an appropriate
time (before the occurrence of immunosuppression) resulting in a significiant reduction of TGFβ activity in KDH-8 tumor tissues
and restoration of IL-2 production from splenocytes of tumor-bearing rats; KDH-8 tumor growth ultimately regressed. In vitro
experiments also showed that TGFβ activity, mRNA expression, and protein synthesis in KDH-8 tumor cells were reduced by bleomycin
treatment, and that bleomycin-treated-KDH-8-tumor-cell-conditioned medium did not inhibit IL-2 production from normal rat
splenocytes. These results suggest that bleomycin treatment restored IL-2 production in tumor-bearing rats through reducing
the tumor-derived TGFβ.
Received: 12 June 1995 / Accepted: 3 November 1995 相似文献
11.
W. Lasek Wojciech Feleszko Jakub Goląb Tomasz Stokłosa Maria Marczak Anna Dąbrowska Magdalena Malejczyk Marek Jakóbisiak 《Cancer immunology, immunotherapy : CII》1997,45(2):100-108
There is strong evidence that antitumor activity of interleukin-12 (IL-12) in vivo is mediated, in part, through interferon
(IFNγ) produced by IL-12-stimulated natural killer and T cells. Since IFNγ and tumor necrosis factor α (TNFα) have been reported
to synergize in antitumor effects in a number of models, we decided to examine whether the combined treatment with recombinant
mouse IL-12 and recombinant human TNFα would produce similar effects. The efficacy of the combined IL-12/TNFα immunotherapy
was evaluated in three tumor models in mice: B16F10 melanoma, Lewis lung (LL/2) carcinoma and L1 sarcoma. Intratumoral daily
injections of 1 μg IL-12 in combination with 5 μg TNFα into B16F10-melanoma-bearing mice resulted in a significant retardation
of the tumor growth as compared with that in controls and in mice treated with either cytokine alone. Similar effects were
obtained using 0.1 μg IL-12 and 5 μg TNFα in LL/2 carcinoma and L1 sarcoma models. Antitumor activity against L1 sarcoma was
still preserved when TNFα at a low dose (1 μg) was combined with 0.1 μg IL-12 and applied for a prolonged time. Potentiation
of antitumor effects, which was observed in IL-12/TNFα-based immunotherapy, could result from at least three different mechanisms,
partly related to stimulation of IFNγ and TNFα production in treated mice: (a) direct cytostatic/cytotoxic effects on tumor
cells, (b) induction of antitumor activity of macrophages, and (c) inhibition of blood vessel formation in the tumor. Our
studies demonstrate that combination tumor immunotherapy with IL-12 and TNFα may be more effective than single-cytokine treatment,
and suggest possible mechanisms by which IL-12 and TNFα may exert potentiated therapeutic effects against locally growing
tumors.
Received: 17 February 1997 / Accepted: 5 August 1997 相似文献
12.
N. J. Meropol Grace M. Barresi Todd A. Fehniger James Hitt Margaret Franklin Michael A. Caligiuri 《Cancer immunology, immunotherapy : CII》1998,46(6):318-326
Natural killer (NK) cells may be expanded in vivo with a prolonged course of daily subcutaneous interleukin-2 (IL-2). However,
cellular activation requires higher concentrations of IL-2 than are achieved with low-dose therapy. The objective of the current
trial was to determine the toxicity and immunological effects of periodic subcutaneous intermediate-dose IL-2 pulses in patients
receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL-2 at 1.25×106 International Units (1.25 MIU) m–2 day–1. After 4–6 weeks, patients received escalating 3-day intermediate-dose IL-2 pulses administered as single daily subcutaneous
injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m–2 day–1, with transient hypotension, fatigue, and nausea/vomiting dose-limiting. Subcutaneous IL-2 resulted in in vivo expansion
of CD56+ NK cells (796±210%) and CD56bright natural killer (NK) cells (3247±1382%). Expanded NK cells coexpressed CD16, and showed lymphokine-activated killer activity
and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrations above
100 pM. Cellular activation was suggested by rapid margination of NK cells following pulsing, coincident with peak IL-2 levels,
with return to baseline by 24 h. In addition, interferon γ production in response to lipopolysaccharide was augmented. Subcutaneous
daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outpatient regimen that results in in vivo expansion
and potential activation of NK cells, with possible application in the treatment of malignancy and immunodeficiency.
Received: 31 December 1997 / Accepted: 20 April 1998 相似文献
13.
Effects of interleukin-12 on in vitro culture with interleukin-2 of regional lymph node lymphocytes from lung cancer patients 总被引:2,自引:0,他引:2
T. Hanagiri Mitsuhiro Takenoyama Takashi Yoshimatsu Chikashi Hirashima Ichiro Yoshino Kozo Nakanishi Akira Nagashima Kikuo Nomoto Kosei Yasumoto 《Cancer immunology, immunotherapy : CII》1996,43(2):87-93
In the present study, we carried out a functional analysis of regional lymph node lymphocytes (RLNL) from patients with lung
cancer after in vitro activation by interleukin-2 (IL-2) and interleukin-12 (IL-12). IL-12 (100 U/ml) enhanced both the proliferation
and cytotoxic activity of RLNL in a culture with low doses of IL-2 (5 – 10 JRU/ml). After comparing an RLNL culture with a
low dose of IL-2 alone, a higher proportion of CD8+ cells and CD56+ cells and a lower proportion of CD4+ cells were found in the culture with both IL-12 and a low dose of IL-2. Such a combination of the cytokines effectively activated
RLNL in terms of the expression of IL-2 receptors. In the culture condition of IL-12 and a low dose of IL-2, a synergistic
effect was observed in the production of such cytokines as interferon γ, tumor necrosis factor α (TNFα), and TNFβ, as well
as in tumor cytotoxicity. However, the addition of IL-12 inhibited the cytotoxicity of RLNL in the culture with a high dose
of IL-2 (100 JRU/ml). This inhibition is considered to be partially due to the endogenous production of TNFα by lymphocytes,
because the neutralization of TNFα bioactivity partially restored the cytotoxic activities of RLNL. Furthermore, in the presence
of hydrocortisone, IL-12 synergistically enhanced the cytotoxic activity of RLNL cultured with a high dose of IL-2. These
results provide useful information about the improvement of adoptive immunotherapy against cancer using RLNL.
Received: 2 February 1996 / Accepted: 30 July 1996 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.
16.
Y. Kikuchi Eiji Imaizumi Yoshitaka Kataoka Junko Hirata Tsunekazu Kita Takehiko Tode Ichiro Nagata 《Cancer immunology, immunotherapy : CII》1997,43(5):257-261
The aim of this study was to elucidate the effect of intraperitoneal (i.p.) instillations of granulocyte-colony-stimulating
factor (G-CSF) and/or interleukin-2 (IL-2) on ascites formation and the survival time of nude mice with malignant ascites,
produced by i.p. inoculation of human ovarian cancer cells. When the nude mice were treated with medium alone, ascites was
observed in all mice 28 days after tumor inoculation. When the mice were treated with cis-diamminedichloroplatinum(II) (cisplatin) alone, G-CSF alone or IL-2 alone, it took 35 days for the ascites to form in all
mice. When cisplatin was combined with G-CSF or IL-2, one of ten mice did not form ascites during the observation period.
Surprisingly, when G-CSF and IL-2 were simultaneously administered, ascites formation was not observed in any mice. Although
i.p. treatment with cisplatin alone significantly prolonged the survival time, compared to medium alone, the lytic activity
of spleen cells against HRA cells was significantly suppressed. When G-CSF or IL-2 was combined with cisplatin, the suppression
by cisplatin was eliminated and subsequently resulted in a prolongation of the survival time. When G-CSF was combined with
IL-2, both the peritoneal and splenic macrophages/monocytes were stimulated and the splenic lytic activity was about double
that following treatment with G-CSF alone on IL-2 alone, suggesting that complete inhibition of ascites formation results
not only from a significant increase of the peritoneal macrophages but also from enhancement of the lytic activity. Two mice,
died from dissemination of tumor in the abdominal cavity, but eight mice survived without tumor for more than 90 days. As
confirmed by monitoring body weight and hematocrit, G-CSF and IL-2 seemed to have no adverse effect. From these results, we
conclude that a combination therapy with G-CSF and IL-2 might be of clinical use for inhibiting large amounts of ascites,
which may inhibit therapeutic effects for ovarian cancer patients.
Received: 20 May 1996 / Accepted: 19 September 1996 相似文献
17.
Rutger L. van Bezooijen H. Goey Gerrit Stoter J. Hermans G. J. Fleuren 《Cancer immunology, immunotherapy : CII》1997,43(5):293-298
Interleukin-2 (IL-2)-based immunotherapy can induce antitumor responses in about 25% of patients with metastatic renal cell
carcinoma (RCC). The limited effect and the severe side-effects of IL-2 have led us to perform a prognostic factor analysis.
Twenty-four patients with metastatic RCC were treated with IL-2. Flow cytometry and immunohistology were used to determine
DNA ploidy, HLA-II expression on tumor cells, and the presence of macrophages in the primary tumor. These variables were examined
in relation to survival. The 4-year overall survival rate was 38%. Forty-six percent of the primary tumors were aneuploid.
All tumors, except one, showed HLA-II expression and macrophage presence. A statistically significant correlation (r = 0.66, P = 0.002) was found between HLA-II expression and macrophage presence. Patients with high HLA-II expression had a lower 4-year
survival (22% compared to 50%), as had patients with high macrophage presence (20% compared to 42%). Of note, patients characterized
by both high HLA-II and high macrophage expression had the worst survival (13% compared to 50%). We concluded that DNA ploidy
was not predictive for survival, whereas HLA-II expression and macrophage presence may represent valuable prognostic factors
related to survival. The present data suggest that more of the patients with no or moderate HLA-II expression and/or no or
moderate macrophage presence in the primary tumor could survive with persistance of their malignant disease after having received
IL-2 immunotherapy, as compared to patients with both high HLA-II and high macrophage expression.
Received: 2 April 1996 / Accepted: 15 October 1996 相似文献
18.
19.
Filiberto Belli Flavio Arienti J. Sulé-Suso C. Clemente Luigi Mascheroni Alessandro Cattelan Cristina Santantonio Gian Francesco Gallino Cecilia Melani Stefania Rao Mario P. Colombo Michele Maio Natale Cascinelli G. Parmiani 《Cancer immunology, immunotherapy : CII》1997,44(4):197-203
From January 1994 to July 1996 we immunized metastatic melanoma patients with HLA-A2-compatible, interleukin-2 (IL-2)-secreting,
immunogenic melanoma lines in an attempt to induce a systemic reaction that might also affect distant melanoma lesions. Twelve
patients (6 male and 6 female) aged from 28 to 72 years, affected with visceral and/or subcutaneous (s.c.) melanoma metastases,
were treated. Two different HLA-A2+ melanoma lines were transduced with the human IL-2 gene (14932/IL-2 and 1B6/IL-2) and used as vaccine. Two groups of 4 patients
each were injected s.c. with 5×107 and 15×107 irradiated 14932/IL-2 melanoma cells respectively, whereas a third group received 5×107 cells of the second line (1B6/IL-2). All patients received the vaccine on days 1, 13, 26; if no progression was evident,
further immunizations were administered at monthly intervals. All patients were assessable for clinical response after at
least three injections of the vaccine. In 4 cases a stabilization of disease lasting from 2 to 6 months was observed; in 2
of them a mixed type of response to treatment was noted with simultaneous evidence of regressing and non-responding lesions
in the same patients. No signs of clinical response were found in the remaining patients. Nine patients died of disease between
3 and 24 months after the onset of therapy, whereas 3 were alive 3 months after the end of therapy. The local and systemic
side-effects of treatment were mild. These results indicate that vaccination with cells bearing the appropriate antigens and
releasing IL-2 locally can produce weak clinical responses, but also indicate that better results may be achieved through
modifications of the vaccine, the schedule of immunization and/or a more appropriate selection of patients.
Received: 20 December 1996 / Accepted: 27 February 1997 相似文献
20.
N. T. Young D. L. Roelen Margaret J. Dallman Peter J. Morris Ken I. Welsh 《Immunogenetics》1998,47(4):310-317
The generation of interleukin-2 (IL-2)-mediated helper activity is a central step in the immune response induced by allogeneic
histocompatibility antigens, and IL-2-producing helper T-lymphocyte precursor (HTLp) frequencies have been proposed as a measure
of alloreactivity in transplant recipients. We analyzed the influence of HLA-matching on the alloresponse of HTLp in limiting
dilution assays derived from healthy individuals. Mean HTLp frequencies were significantly higher in HLA-DR antigen-mismatched
than HLA-DR-matched combinations. Significant differences in the effect of one or two mismatched HLA-DR antigens on mean HTLp
frequencies were also detected. Mean HLA class I (HLA-A, -B, -Cw) mismatches were not significantly different in each group
and had no apparent influence on HTLp frequencies. Analysis of HLA protein sequence disparities revealed no significant difference
in the number of mismatched amino acid residues at the HLA-DRB1 locus between one and two HLA-DR antigen-mismatched combinations
but correlated strongly with HTLp frequency. The positive correlation was evident with mismatched residues in the beta sheet
and alpha helical regions of the HLA-DRB1 molecule, suggesting a predominant influence of bound peptides in the stimulation
of alloreactive helper cells. This finding was supported by analysis of the location of individual residue mismatches. Evidence
of an effect of polymorphism in the CD4-binding region in the β-2 domain of HLA-DRB1 molecules was also found. Our results
demonstrate the major influence of HLA-DR amino acid sequence mismatching on alloreactive HTLp frequencies but also suggest
that additional genetic or environmental influences affect the alloreactive helper T-cell repertoire.
Received: 2 September 1997 / Revised: 29 September 1997 相似文献