共查询到20条相似文献,搜索用时 93 毫秒
1.
T. Sakurai Muneo Yamada Seiichi Simamura Kazuo Motoyoshi 《Cancer immunology, immunotherapy : CII》1997,44(1):48-54
We studied the effect of recombinant human macrophage-colony-stimulating factor (rhM-CSF) on the formation of lung and liver
metastases following the i.v. injection of the B16 melanoma subline (B16 LiLu) into mice. When rhM-CSF was administered before
the B16 inoculation, the number of tumor metastases decreased in the lung and liver. However, the administration of rhM-CSF
after B16 inoculation did not produce an antimetastatic effect in the lung, but did in the liver. B16 cells labeled with 5-[125I]-iodo-2′-deoxyuridine (125I-dUrd) were injected and the arrest of tumor cell emboli was examined in the capillary beds of the lung and liver of mice
treated with either vehicle or rhM-CSF. In both groups, there were the same numbers of B16 cells in both the lung and the
liver 3 minutes after the B16 injection, and almost all tumor cells died within 24 h. However, the number of cells surviving
in the lung was decreased in mice injected with rhM-CSF (37%). There was no difference in the number of cells in the livers
of mice treated either with vehicle or rhM-CSF in the first 24 h after tumor cell injection. The administration of rhM-CSF
increased NK 1.1+ cells in the mouse spleen and facilitated NK activity in vivo. At the same time, the administration of an anti-NK 1.1 antibody
blocked the antimetastatic effect of rhM-CSF in the lung but not in the liver. The antibody was effective only when it was
injected before the B16 inoculation. These results suggest that the antimetastatic effect of rhM-CSF in the lung was mediated
by NK 1.1+ cells within 24 h of B16 injection. In contrast, the antimetastatic effect of rhM-CSF in the liver was mediated not only
by NK 1.1+ cells but also by other antimetastatic systems such as macrophages.
Received: 8 April 1996 / Accepted: 26 November 1996 相似文献
2.
Tumor-derived Fas ligand induces toxicity in lymphoid organs and plays an important role in successful chemotherapy 总被引:7,自引:0,他引:7
Nagarkatti N 《Cancer immunology, immunotherapy : CII》2000,49(1):46-55
Recent studies have suggested that Fas ligand (FasL+) tumor cells can induce apoptosis in Fas+ T cells. However, the effect of growth of FasL+ tumors in vivo, on lymphoid tissues of the host is not clear and therefore was the subject of this investigation. Injection
of FasL+ LSA tumor caused a significant decrease in cellularity of the thymus and spleen, resulting from marked apoptosis, in syngeneic
C57BL/6+/+ (wild-type) but not C57BL/6-lpr/lpr (Fas-deficient) mice. The tumor-induced toxicity resulted from tumor-derived rather than host-derived FasL, inasmuch as LSA
tumor growth in C57BL/6-gld/gld (FasL-defective) mice, induced marked apoptosis and toxicity in the thymus and spleen. The LSA tumor growth induced a significant
decrease in the percentage of CD4+CD8+ T cells in the thymus of C57BL/6+/+ mice and an increase in the percentage of CD4+, CD8+ and CD4−CD8− T cells. Of the four subpopulations tested, the CD4+CD8+ T cells showed maximum apoptosis. The LSA (FasL+) but not P815(FasL−) tumor cell lysates and culture supernatants induced marked apoptosis in Fas+ thymocytes, when tested both in vitro and in vivo. The LSA-tumor-induced apoptosis in vitro was inhibited by antibodies against
FasL or by caspase and other inhibitors of apoptosis. Chemotherapy of LSA-tumor-bearing C57BL/6+/+ mice at advanced stages
of tumor growth failed to cure the mice, whereas, more than 80% of LSA-tumor-bearing C57BL/6-lpr/lpr mice, similarly treated, survived. Together, the current study demonstrates that FasL produced by LSA tumor cells is functional
in vivo and can cause severe toxicity in lymphoid organs of the host. Also, Fas/FasL interactions may play an important role
in the successful chemotherapy of FasL-bearing tumor.
Received: 31 August 1999 / Accepted: 12 November 1999 相似文献
3.
Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model 总被引:2,自引:0,他引:2
Kazuki Yamanaka Isao Hara Hiroshi Nagai Hideaki Miyake Kazuo Gohji Mark J. Micallef Masashi Kurimoto Soichi Arakawa Sadao Kamidono 《Cancer immunology, immunotherapy : CII》1999,48(6):297-302
We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete
bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent
syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient
mice whose CD8+ T or CD4+ T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1
antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed
MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration.
This synergism was abrogated when the mice were treated with interferon-γ-neutralizing antibody in vivo. In conclusion, local
secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-γ
plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.
Received: 7 May 1998 / Accepted: 27 May 1999 相似文献
4.
M. Klokker N. H. Secher P. Madsen H. L. Olesen S. Matzen U. Knigge J. Warberg B. K. Pedersen 《European journal of applied physiology and occupational physiology》1997,76(5):415-420
To evaluate a possible role for β-endorphin in the stress-induced modulation of natural killer (NK) cells, immunologically
competent blood cells were followed in eight male volunteers administered either Naloxone or saline (control) during head-up
tilt maintained until the appearance of presyncopal symptoms (PS). The PS appeared more rapidly with Naloxone compared to
control [5.7 (SEM 1.1) vs 22.3 (SEM 5.1) min; P = 0.01]. The NK cell activity increased threefold during PS partly due to an increase in CD16+ and CD56+ NK cells in blood. In support, NK cell activity boosted with interferon-α and interleukin 2 rose in parallel with unboosted
NK cell activity and NK cell concentration and activities returned to the baseline level after 105 min. The total lymphocyte
count and the concentrations of CD3+, CD4+, CD8+, CD16+, and CD56+ cells increased during PS. Head-up tilt also induced an increase in plasma adrenaline concentration during control PS and
a rise in plasma cortisol and adrenocorticotropic hormone concentrations up to 30 min thereafter, whereas no significant changes
were found in plasma concentrations of noradrenaline, growth hormone, or β-endorphin. The results would indicate an influence
of endorphin on the increase in plasma adrenaline concentration during head-up tilt and at the same time contra-indicate a
significant role for adrenaline in the provocation of PS. The influence of head-up tilt on plasma β-endorphin was too small
to influence the modulation of the cellular immune system.
Accepted: 22 May 1997 相似文献
5.
Ursula Grohmann Maria Laura Belladonna Roberta Bianchi Ciriana Orabona Silvia Silla Giuseppe Squillacioti Maria Cristina Fioretti Paolo Puccetti 《Cancer immunology, immunotherapy : CII》1999,48(4):195-203
Nonameric P815AB, a cytotoxic-T-lymphocyte-defined minimal core peptide encoded by the murine mastocytoma gene P1A, fails to initiate CD4+ cell-dependent reactivity in vivo to class-I-restricted epitopes when mice are administered peptide-pulsed dendritic cells.
Effective immunization requires T helper effects, such as those mediated by coimmunization with class-II-restricted (helper)
peptides or by the use of recombinant interleukin-12 (rIL-12). Although P815AB does possess class-II-restricted epitopes,
they are likely suboptimal, resulting in poor affinity and/or stability of MHC/P815AB complexes and inadequate activation
of the antigen-presenting cell function of dendritic cells. The present study has examined a series of longer, P815AB-centered
peptides (11–14 amino acids in length, all P1A-encoded) for their ability to initiate CD4+ and CD8+ cell-mediated responses to the nonamer in vivo, their ability to bind class II MHC in vitro, and their ability to assemble
class II molecules stably. By means of a class-I-restricted skin test assay in mice receiving peptide-pulsed dendritic cells,
we found that a 12-mer and a 13-mer effectively immunized against the core P815AB peptide, and that this correlated with IL-2
production in vitro by CD4+ cells in response to the nonamer. In vitro studies, involving affinity-purified class II molecules, showed that the capacity
to assemble class II molecules stably, more than the affinity for class II MHC, correlated with the ability of the different
P815AB peptides to prime the host to the core peptide seen by the T cells.
Received: 25 February 1999 / Accepted: 14 April 1999 相似文献
6.
Lees CJ Apostolopoulos V Acres B Ong CS Popovski V McKenzie IF 《Cancer immunology, immunotherapy : CII》2000,48(11):644-652
MUC1 is a mucin over-expressed in breast cancer and a proposed target for immunotherapy. By immunising mice with MUC1 conjugated
to mannan (M-FP), CD8+ MHC-class-I restricted cytotoxic T lymphocytes (CTL), of high CTL precursor (CTLp) frequency (1/8000) and with significant
tumour protection, can be induced. The effect of various cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-7, interferon γ (IFNγ),
and granulocyte/macrophage-colony-stimulating factor (GM-CSF)] on the MUC1 CTL immune response was investigated (a) by measuring
the frequencies of CTLp in mice immunised with vaccinia virus constructs containing recombinant cytokines and M-FP, or (b)
by immunising cytokine- or cytokine-receptor-knockout (−/−) mice with M-FP. Vaccinia virus (VV) constructs containing recombinant
cytokines were used either individually or in combination in vivo with M-FP immunisation. M-FP immunisations combined with
VV-IL-2, VV-IL-7 and VV-GM-CSF, and combinations of VV-IFNγ + VV-IL-2, VV-IFNγ + VV-IL-4 or VV-GM-CSF + VV-IL-7 increased
CTLp frequencies up to threefold (1/17 666: M-FP + VV-GM-CSF + VV-IL-7) compared to M-FP (1/77 500) alone. By contrast, M-FP
combined with VV-IL-4 decreased the CTLp frequency threefold whereas VV-IL-6 and VV-IFNγ had no effect. Studies in cytokine-
and cytokine-receptor-gene-knockout (−/−) mice demonstrated that mice that are IL-2 −/− and IL-7 receptor −/− produce the
same CTLp response to M-FP as do control mice, whereas responses in the IL-6 −/−, IL-10 −/− and IFNγ−/− mice were marginally
improved and responses to M-FP in IL-4 −/− and tumour necrosis factor receptor 2 −/− mice were weaker. In spite of the increase
in CTLp frequency, this was not reflected in an in vivo tumour model. Tumour challenges using MUC1+ P815 cells, demonstrated that the addition of cytokines had little additive effect on the already effective tumour-regression
capabilities of M-FP alone.
Received: 24 September 1998 / Accepted: 21 September 1999 相似文献
7.
Kimura K Nishimura H Matsuzaki T Yokokura T Nimura Y Yoshikai Y 《Cancer immunology, immunotherapy : CII》2000,49(2):71-77
Interleukin(IL)-15, which uses IL-2 receptor (R) β and γ chains for signal transduction, shares many of the biological activities
of IL-2. We examined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and
syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival time of mice
after an intrapleural inoculation of MethA, whereas the same dose of IL-2 did not. The in vivo antitumor effect of IL-15 was
synergistically enhanced by additive administration of IL-12. Combination therapy of IL-15 and IL-12 protected mice from death
from bloody pleural fluid. Such treatment induced marked increases in the number of CD3-IL-2Rβ+ cells corresponding to natural killer (NK) cells and the production of interferon γ (IFNγ) by T cells in the thoracic exudate
cells (TEC). Administration of anti-IFNγ mAb partly inhibited the protective effect of a combination of IL-15 and IL-12. A
tumor-neutralizing (Winn) assay revealed that the antitumor activity of effector cells in the TEC was abrogated by treatment
with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatment with IL-15 in combination with IL-12 may enhance the
activities of NK and CD8+ T cells in the TEC, providing strong antitumor activity against the malignant pleurisy. These results suggest that IL-15
together with IL-12 may have potential for the immunotherapy of some types of malignant pleurisy.
Received: 13 July 1999 / Accepted: 3 December 1999 相似文献
8.
Anne R. Amoroso R. Katherine Alpaugh Malcolm W. Barth Adrian M. McCall Louis M. Weiner 《Cancer immunology, immunotherapy : CII》1999,48(8):443-455
Fcγ receptor (FcγR) engagement is pivotal for many effector functions of macrophages, polymorphonuclear neutrophils (PMN),
and natural killer (NK) cells. Mice transgenic for the A and B isoforms of human (h) FcγRIII on macrophages, PMN, and NK cells
were constructed to permit the study of mechanisms and potential in vivo strategies to utilize the cytotoxic effector and
antigen-presenting functions of cells expressing the hFcγR. The present report characterizes the phenotypic and functional
expression of hFcγRIII in transgenic mice derived by crossing hFcγRIIIA and hFcγRIIIB transgenic mice. Interleukin-2 (IL-2)
induces hFcγRIII expression by myeloid cells and their precursors, and these transgenic receptors promote in vitro cytotoxicity
and anti-hFcγRIII antibody internalization. Splenocytes from untreated and IL-2-treated hFcγRIIIA, hFcγRIIIB, and hFcγRIIIA/B
mice exhibited enhanced in vitro cytotoxicity toward HER-2/neu-overexpressing SK-OV-3 human ovarian carcinoma cells when incubated with the murine bispecific mAb 2B1, which has specificity
for HER-2/neu and hFcγRIII. These results indicate that hFcγRIII transgenes are expressed on relevant murine cellular subsets, exhibit
inducible up-regulation patterns similar to those seen in humans, and code for functional proteins. hFcγRIII transgenic mice
exhibiting specific cellular subset expression will permit the examination of strategies designed to enhance hFcγRIII-dependent
immunological effector functions and will provide a model system in which to evaluate preclinically potential candidate molecules
that recognize hFcγRIII for the immunotherapy of cancer.
Received: 5 December 1998 / Accepted: 14 July 1999 相似文献
9.
M. J. Micallef Kenshi Yoshida Sachiko Kawai Toshiharu Hanaya Keizo Kohno Shigeyuki Arai Tadao Tanimoto Kakuji Torigoe Mitsukiyo Fujii Masao Ikeda Masashi Kurimoto 《Cancer immunology, immunotherapy : CII》1997,43(6):361-367
Interferon-γ-inducing factor/interleukin-18 is a novel cytokine that reportedly augments natural killer (NK) activity in
human and mouse peripheral blood mononuclear cell cultures in vitro and has recently been designated IL-18. In this study,
IL-18 exhibited significant antitumor effects in BALB/c mice challenged intraperitoneally (i.p.) with syngeneic Meth A sarcoma
when administered i.p. on days 1, 2 and 3 after challenge. Intravenous (i.v.) administration also induced antitumor effects
in the tumor-bearing mice; however, subcutaneous (s.c.) administration did not. When mice were twice pretreated with 1 μg
IL-18 3 days and 6 h before tumor challenge, all mice survived whereas control mice died within 3 weeks of challenge. Inhibitory
effects on Meth A cell growth in vitro were not observed with either IL-18 or interferon γ. The effects of IL-18 pretreatment
were abrogated by abolition of NK activity after mice had been injected with anti-asialo GM1 antibody 48 h before and, 24
h and 72 h after tumor challenge. Mice pretreated with IL-18 and surviving tumor challenge resisted rechallenge with Meth
A cells but could not reject Ehrlich ascites carcinoma, and spleen cells from the resistant mice, but not control mice, exhibited
cytotoxic activity against Meth A cells in vitro after restimulation with mitomycin C-treated Meth A cells for 5 days. The
effector cells in the spleen cell preparations from resistant mice appear to be CD4+ cells because cytolytic activity was significantly inhibited after depletion of this subset by monoclonal antibodies and
complement. In conclusion, IL-18 exhibits in vivo immunologically (primarily NK) mediated antitumor effects in mice challenged
with syngeneic Meth A sarcoma and induces immunological memory and the generation of cytotoxic CD4+ cells.
Received: 17 September 1996 / Accepted: 8 November 1996 相似文献
10.
Blank Sally E.; Jones T. Bucky; Lee Eric G.; Brahler C. Jayne; Gallucci Randle M.; Fox Marne L.; Meadows Gary G. 《Journal of applied physiology》1997,83(3):845-850
Blank, Sally E., T. Bucky Jones, Eric G. Lee, C. JayneBrahler, Randle M. Gallucci, Marne L. Fox, and Gary G. Meadows. Modulation of NK cell cytolytic activity by macrophages in chronically exercise-stressed mice. J. Appl.Physiol. 83(3): 845-850, 1997.This study wasdesigned to investigate the effects of moderate-intensity endurancetraining on basal natural killer (NK) cell cytolytic activity in murinesplenocytes that were enriched for1)NK1.1+ cells or2) macrophages andNK1.1+ cells. Mice were assignedto sedentary (Sed), treadmill control (TM), or treadmill-trained (Trn)groups. Splenocyte number, the percentages ofNK1.1+, large granular lymphocytes(NK1.1+, LGL-1+),and other subpopulations did not change in Trn mice. Approximately 70%of cells enriched for NK1.1+expressed this surface antigen. Lytic units (LU) expressed per LGL-1+ cell were significantlylower in Trn [83.9 ± 3.2 (SE)] compared with Sed (109.5 ± 7.5) and TM (101.3 ± 6.4) groups. When macrophages remainedin the in vitro assay, LU perLGL-1+ cell did not differ acrossgroups. The results indicate that highly enrichedNK1.1+ cells from Trn mice hadlower NK cell activity compared with Sed mice. No differences in NKcell activity were observed when cells were enriched forNK1.1+ cells and macrophages.These findings support the hypothesis that macrophage modulation of NKcells may be one mechanism contributing to augmented basal NK cellactivity in endurance-trained individuals. 相似文献
11.
Keiichi Moriya Ayako Wakabayashi Masumi Shimizu Hideto Tamura Kazuo Dan Hidemi Takahashi 《Cancer immunology, immunotherapy : CII》2010,59(7):1083-1095
Two major distinct subsets of dendritic cells (DCs) are arranged to regulate our immune responses in vivo; 33D1+ and DEC-205+ DCs. Using anti-33D1-specific monoclonal antibody, 33D1+ DCs were successfully depleted from C57BL/6 mice. When 33D1+ DC-depleted mice were stimulated with LPS, serum IL-12, but not IL-10 secretion that may be mediated by the remaining DEC-205+ DCs was markedly enhanced, which may induce Th1 dominancy upon TLR signaling. The 33D1+ DC-depleted mice, implanted with syngeneic Hepa1-6 hepatoma or B16-F10 melanoma cells into the dermis, showed apparent inhibition
of already established tumor growth in vivo when they were subcutaneously (sc) injected once or twice with LPS after tumor
implantation. Moreover, the development of lung metastasis of B16-F10 melanoma cells injected intravenously was also suppressed
when 33D1+ DC-deleted mice were stimulated twice with LPS in a similar manner, in which the actual cell number of NK1.1+CD3− NK cells in lung tissues was markedly increased. Furthermore, intraperitoneal (ip) administration of a very small amount
of melphalan (l-phenylalanine mustard; l-PAM) (0.25 mg/kg) in LPS-stimulated 33D1+ DC-deleted mice helped to induce H-2Kb-restricted epitope-specific CD8+ cytotoxic T lymphocytes (CTLs) among tumor-infiltrating lymphocytes against already established syngeneic E.G7-OVA lymphoma.
These findings indicate the importance and effectiveness of selective targeting of a specific subset of DCs, such as DEC-205+ DCs alone or with a very small amount of anticancer drugs to activate both CD8+ CTLs and NK effectors without externally added tumor antigen stimulation in vivo and provide a new direction for tumor immunotherapy. 相似文献
12.
Three mouse killer immunoglobulin-like receptors (KIRs), namely, KIR3DL1, KIRL1, and KIRL2, have recently been identified
in C56BL/6 (B6) mice. However, only two Kir genes are found in the B6 mouse genome sequence data base. To clarify this discrepancy, we cloned Kir cDNAs from multiple strains of mice. Sequencing of the cDNA clones showed that the Kir3dl1 gene is found in C3H/HeJ and CBA/J but not in B6 mice. Analysis of the single nucleotide polymorphism data base suggested
that Kir3dl1 is the C3H/HeJ and CBA/J allele of Kirl1. We generated mAb to the recombinant KIRL1 protein to investigate its expression pattern. The anti-KIRL1 mAb bound to NK1.1+ T cells but only very weakly or at undetectable levels to other lymphocytes including natural killer (NK) cells and conventional
T cells. Among NK1.1+ T cells, conventional NK T cells stained with CD1d tetramer did not significantly bind anti-KIRL1 mAb, whereas CD1d-tetramer-negative
subset was KIRL1-positive. Furthermore, the expression of KIRL1 is readily detected on NK1.1+ T cells from β2-microglobulin-deficient B6 mice. Thus, KIRL1 is predominantly expressed on CD1d-independent NK1.1+ T cells. 相似文献
13.
Abdullah N Greenman J Pimenidou A Topping KP Monson JR 《Cancer immunology, immunotherapy : CII》1999,48(9):517-524
Monocytes and natural killer (NK) cells are known to be important effector cell populations in mediating antibody-dependent
cell-mediated cytotoxicity (ADCC). Purified monocyte and NK effector cell populations, from normal and colorectal cancer (CRC)
patients, together with a number of murine (17-1A and 323/A3) and their chimaeric (c17-1A) or humanised (3622W94) equivalents,
and chimaeric (c) SF25 were compared for their ability to mediate ADCC of colorectal tumour cells. The chimaeric and humanised
antibodies were significantly better at mediating tumour lysis than their murine equivalents with all-effector populations.
When effector cells from CRC patients were used the cSF25 antibody was significantly better than 3622W94 (P < 0.02) which, in turn, was significantly better than c17-1A (P < 0.03). Depletion of NK cells produced a decrease in specific tumour lysis with all antibodies. In addition a higher rate of
NK cell death was observed in CRC patients during the assay than in normal controls. The chimaeric and humanised antibodies
stained a similar percentage of the HT-29 target cells (>80%), but 3622W94 bound to significantly more cells from primary
tumour biopsies than cSF-25 (P = 0.001). Together, the results suggest that NK cells are the most important effector cell type mediating ADCC in vitro,
that there is some impairment of NK function in CRC patients, and that cSF25 is the most potent antibody. For use in vivo
the anti-Ep-CAM antibody 3622W94 would appear to be the most suitable reagent for further study.
Received: 3 June 1999 / Accepted: 22 July 1999 相似文献
14.
H. J. McKenna 《Cancer immunology, immunotherapy : CII》1999,48(6):281-286
flt3 ligand (FL) is a growth factor that induces hematopoietic progenitor cell and dendritic cell (DC) expansion when administered
to mice. Lymphoid-related (CD8α+) and myeloid-related (CD8α−) DC are transiently expanded in multiple tissues. Treatment of tumor-bearing mice with FL results in slower tumor growth
and, in some cases, tumor rejection and the development of tumor-specific T cell immunity. The clinical use of DC as cellular
vehicles for tumor antigen presentation to generate a tumor-specific T cell response is under investigation. DC are currently
generated ex vivo, pulsed with antigen, and then infused into patients, and much effort is being directed toward optimizing
each of these steps. Administration of FL to humans induces a profound increase in circulating DC. The availability of a large
number of DC generated in vivo has important implications for tumor immunotherapy approaches.
Received: 13 May 1999 / Accepted: 14 June 1999 相似文献
15.
Dowell AC Oldham KA Bhatt RI Lee SP Searle PF 《Cancer immunology, immunotherapy : CII》2012,61(5):615-628
4-1BB ligation co-stimulates T cell activation, and agonistic antibodies have entered clinical trials. Natural killer (NK)
cells also express 4-1BB following activation and are implicated in the anti-tumour efficacy of 4-1BB stimulation in mice;
however, the response of human NK cells to 4-1BB stimulation is not clearly defined. Stimulation of non-adherent PBMC with
OVCAR-3 cells expressing 4-1BB ligand (4-1BBL) or IL-12 resulted in preferential expansion of the NK cell population, while
the combination 4-1BBL + IL-12 was superior for the activation and proliferation of functional NK cells from healthy donors
and patients with renal cell or ovarian carcinoma, supporting long-term (21 day) NK cell proliferation. The expanded NK cells
are predominantly CD56bright, and we show that isolated CD56dimCD16+ NK cells can switch to a CD56brightCD16− phenotype and proliferate in response to 4-1BBL + IL-12. Whereas 4-1BB upregulation on NK cells in response to 4-1BBL required
‘help’ from other PBMC, it could be induced on isolated NK cells by IL-12, but only in the presence of target (OVCAR-3) cells.
Following primary stimulation with OVCAR-3 cells expressing 4-1BBL + IL-12 and subsequent resting until day 21, NK cells remained
predominantly CD56bright and retained both high cytotoxic capability against K562 targets and enhanced ability to produce IFNγ relative to NK cells
in PBMC. These data support the concept that NK cells could contribute to anti-tumour activity of 4-1BB agonists in humans
and suggest that combining 4-1BB-stimulation with IL-12 could be beneficial for ex vivo or in vivo expansion and activation
of NK cells for cancer immunotherapy. 相似文献
16.
Akihiro Tsukahara Hiroki Kawamura Tsuneo Iiai Tetsuya Moroda Susumu Suzuki Takashi Tada Masahiro Minagawa Nobuyuki Musha Katsuyoshi Hatakeyama Toru Abo 《Microbiology and immunology》1998,42(6):447-456
When C57BL/6 (B6) mice were irradiated (9 Gy) and received bone marrow (BM) cells of B6-lpr/lpr mouse origin (i.e., lpr→B6), all mice died within 6 days. In the irradiated B6 mice, radioresistant CD3? IL-2Rβ+ NK cells and IL-2Rβ CD3int cells (i.e., CD3int cells of extrathymic origin) remained, especially in the liver. There were two subsets, NK1.1+ and NK1.1?, among the IL-2Rβ+ CD3int cells. However, the NK1.1+ subset (i.e., NK1.1+ T cells) was much more radioresistant, and the majority of CD3int cells belonged to this subset in irradiated mice. The expansion of lymphocytes from injected BM cells did not occur in the irradiated B6 mice. However, such expansion did take place in irradiated B6-lpr/lpr mice injected with both BM cells of B6-lpr/lpr and B6 origin. As a result, the mice subjected to BM cells survived. Irradiated B6 mice were treated in vivo with anti-NK1.1 mAb or anti-asialoGM1 antibody to eliminate NK cells alone or both NK cells and NK1.1+ T cells. When irradiated B6 mice were pretreated with anti-NK1.1 mAb, the mice could survive. These results suggest that intact NK1.1+ T cells of extrathymic origin may recognize abnormal BM cells with the lpr gene and inhibit the expansion of lymphocytes, including abnormal double-negative CD4?8? cells, in B6-lpr/lpr mice. To inhibit the expansion of lymphocytes, mechanisms other than Fas ligand/Fas molecules on extrathymic T cells may be responsible. 相似文献
17.
Antitumor effect of heat-killed Lactobacillus plantarum L-137 through restoration of impaired interleukin-12 production in tumor-bearing mice 总被引:4,自引:0,他引:4
Murosaki S Muroyama K Yamamoto Y Yoshikai Y 《Cancer immunology, immunotherapy : CII》2000,49(3):157-164
We have previously reported that heat-killed Lactobacillus plantarum L-137 is a potent inducer of interleukin-12 (IL-12) in vivo as well as in vitro in mice. In order to develop effective usage
of L. plantarum L-137 for tumor immunotherapy, we examined its antitumor effect against DBA/2 mice inoculated with syngenic P388D1 tumor
cells in different treatment schedules. Daily injection of L. plantarum L-137 from the day of tumor inoculation induced a steep increase in plasma IL-12 only after the first injection but not after
subsequent injections, and had no effect on tumor growth and survival time. In contrast, daily injection of L. plantarum L-137 from the 7th day after tumor inoculation exerted a marked antitumor effect but such an effect was not evident in mice
treated with L. plantarum L-137 twice a week from the 7th day. IL-12 production was considerably impaired at the first injection but steeply increased
after the third injection in the mice injected daily with L. plantarum L-137 from the 7th day. Our results suggest that daily administration of L. plantarum L-137 is required to exert an antitumor effect at the late stages of tumor development when IL-12 production is considerably
impaired.
Received: 15 July 1999 / Accepted: 28 January 2000 相似文献
18.
19.
《Cytotherapy》2021,23(9):799-809
Background aimsTracking administered natural killer (NK) cells in vivo is critical for developing an effective NK cell-based immunotherapy against human hepatocellular carcinoma (HCC). Here the authors established a new molecular imaging using ex vivo-activated NK cells and investigated real-time biodistribution of administered NK cells during HCC progression.MethodsEx vivo-expanded NK cells from healthy donors were labeled with a near-infrared lipophilic cytoplasmic dye, and their proliferation, surface receptor expression and cytotoxicity activity were evaluated. Human HCC HepG2 cells were implanted into the livers of NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NSG) mice. The authors administered 1,1’-dioctadecyltetramethyl indotricarbocyanine iodide (DiR)-labeled NK cells intravenously to non-tumor-bearing and intrahepatic HCC tumor-bearing NSG mice. Fluorescent imaging was performed using a fluorescence-labeled organism bioimaging instrument. Single cell suspensions from the resected organs were analyzed using flow cytometry.ResultsThe fluorescent DiR dye was nontoxic and did not affect the proliferation or surface receptor expression levels of the NK cells, even at high doses. The administered DiR-labeled NK cells immediately migrated to the lungs of the non-tumor-bearing NSG mice, with increased NK cell signals evident in the liver and spleen after 4 h. NK cells migrated to the intrahepatic tumor-bearing livers of both early- and late-stage HCC mice within 1 h of injection. In early-stage intrahepatic tumor-bearing mice, the fluorescence signal increased in the liver until 48 h post-injection and decreased 7 days after NK injection. In late-stage HCC, the NK cell fluorescence signal was the highest in the liver for 7 days after NK injection and persisted for 14 days. The purity of long-term persistent CD45+CD56+CD3− NK cells was highest in early- and late-stage HepG2-bearing liver compared with normal liver 2 weeks after NK injection, whereas highest purity was still observed in the lungs of non-tumor-bearing mice. In addition, Ki-67 expression was detected in migrated human NK cells in the liver and lung up to 72 h after administration. With HepG2 tumor progression, NK cells reduced the expression of NKp30 and NKG2D.ConclusionsAdministered NK cells were successfully tracked in vivo by labeling the NK cells with near-infrared DiR dye. Highly expanded, activated NK cells migrated rapidly to the tumor-bearing liver, where they persisted for 14 days after administration, with high purity of CD45+CD56+CD3− NK cells. Liver biodistribution and persistence of administered NK cells showed significantly different accumulation patterns during HCC progression. 相似文献
20.
CD58/LFA-3 and IL-12 provided by activated monocytes are critical in the in vitro expansion of CD56+ T cells 总被引:9,自引:0,他引:9
A small proportion of human CD3+ T lymphocytes are known to co-express CD56, an antigen usually restricted in its expression to natural killer (NK) cells.
Whereas the in vivo function of CD3+ CD56+ T cells remains unknown, we and others have previously shown that both in vitro and in vivo, these cells can mediate a significantly
greater degree of MHC-unrestricted cytotoxicity against a variety of human tumor cells when compared to either CD3+ CD56− T cells or lymphokine activated killer (LAK) cells. While the mechanisms regulating the in vivo expansion of CD56+ T cells are not known, here we demonstrate the importance of CD2-mediated IL-12-dependent signals in the in vitro expansion
of CD56+ T cells. Specifically, we show that activated monocytes provide a contact dependent factor (CD58/LFA-3) and a soluble factor
(IL-12), both critical for the in vitro expansion of CD56+ T cells. The biological and therapeutic implications of these findings are discussed.
Received: 4 May 2000 / Accepted: 25 August 2000 相似文献