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1.
Koji Tamada M. Harada Koichiro Abe Tieli Li Hitoshi Tada Yasuhiro Onoe Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1998,46(3):128-136
In order to enhance the antitumor vaccination effect of dendritic cells (DC) pulsed with class I tumor peptide, we tried
to utilize the local cytokine help of CD4+ T cells reactive to a streptococcal preparation OK432. DC were prepared from murine bone marrow cells by culture with both
granulocyte/macrophage-colony-stimulating factor and interleukin(IL)-4. The peritumoral injections of OK432 induced OK432-reactive
CD4+ T cells in the draining lymph nodes, and their in vitro production of interferon γ was thus significantly enhanced by restimulation
with OK432-pulsed DC. In addition, anti-P815 mastocytoma cytotoxic T lymphocytes were generated from the in vivo OK432-treated
P815-draining lymph node cells only when the lymph node cells were restimulated in vitro with the DC pulsed with both P1A
peptide and OK432. Moreover, the peritumoral injections of OK432 and the subsequent vaccination of the DC, pulsed with both
OK432 and P1A peptide, significantly suppressed the growth of s.c. inoculated P815. Interestingly, a significant level of
IL-12 was detected in the coculture supernatant of both OK432-pulsed DC and OK432-reactive CD4+ T cells. Collectively, our results suggest that the antitumor vaccination effect of DC pulsed with class I tumor peptide
could thus be effectively augmented by locally utilizing the Th1-type cytokines from OK432-reactive CD4+ T cells.
Received: 18 July 1997 / Accepted: 23 December 1997 相似文献
2.
Dendritic-cell-peptide immunization provides immunoprotection against bcr-abl -positive leukemia in mice 总被引:12,自引:0,他引:12
He L Feng H Raymond A Kreeger M Zeng Y Graner M Whitesell L Katsanis E 《Cancer immunology, immunotherapy : CII》2001,50(1):31-40
Chronic myelogenous leukemia (CML) is a clonal disorder characterized by proliferation of cells that possess the bcr-abl fusion gene resulting in the production of one of two possible chimeric 210-kDa tyrosine kinase proteins. Since these chimeric
proteins are expressed only in leukemic cells they have the potential to serve as tumor-specific antigens for cytotoxic T
lymphocytes (CTL). Using the 12B1 murine leukemia cell line, derived by retroviral transformation of BALB/c bone marrow cells
with the bcr-abl (b3a2) fusion gene, we have demonstrated that intravenous inoculation of 12B1 cells into BALB/c mice results in a disseminated
acute leukemia analogous to human CML in blast crisis. Histological sections of liver and spleen and polymerase chain reaction
analysis of peripheral blood, bone marrow, liver, spleen and lymph nodes confirmed the presence of bcr-abl
+ leukemia cells in these murine tissues, while Western blot data demonstrated the expression of the fusion protein in 12B1
cells. Immunization of mice with dendritic cells (DC) loaded with the synthetic bcr-abl chimeric nonapeptide, GFKQSSKAL, led to a 150 times higher frequency of bcr-abl-specific CTL precursors in the spleen than in mice immunized with peptide alone. In vitro re-stimulation of DC-peptide-primed
splenocytes resulted in substantial secretion of interferon γ and augmented cytolytic activity against 12B1 targets. Finally,
vaccination with peptide-loaded DC significantly prolonged survival of BALB/c mice that were challenged with 12B1 leukemia.
The capacity to generate bcr-abl-specific CTL in vivo by DC-based immunization may have clinical implications in the treatment of CML.
Received: 14 July 2000 / Accepted: 18 October 2000 相似文献
3.
Iwase S Tsujimura K Matsudaira Y Ozeki S Onozaki K Obata Y Takahashi T 《Microbiology and immunology》2000,44(7):609-618
When the skin of Tg.Con.3-1 transgenic mice expressing the TL (thymus leukemia) antigen in most tissues is grafted on syngeneic C3H mice, it is rejected, and a cytotoxic T cell (CTL) response against the TL antigen is induced. In this study, we first demonstrated that growth of TL positive lymphoma is suppressed in mice immunized by skin grafting. Immunization with bone marrow derived dendritic cells (DCs) from Tg.Con.3-1, was also found to be associated with an anti-tumor response, but less potent than skin grafting. Relative CTL precursor frequency with DC immunization was also approximately only one third that of skin grafting. The numbers of IFN-gamma producing cells in responder CD8 and CD4 T cell populations were higher with DC immunization than with skin grafting. However, DC immunization seems to induce non-specific immune responses, as re-stimulation with TL negative C3H spleen cells resulted in induction of almost half the number observed with TL positive cells. Thus, the actual number of IFN-gamma producing cells in specific responses to TL is not necessarily larger than with skin grafting immunization. The present results altogether suggest that DC immunization is capable of inducing an anti-tumor reaction, but also possibly unwanted immune responses. In vitro monitoring of specific and non-specific responses in the immune system, thus, is of particular importance for future development of cancer immunotherapy. 相似文献
4.
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
5.
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
6.
Homing of intravenously and intralymphatically injected human dendritic cells generated in vitro from CD34+ hematopoietic progenitor cells 总被引:6,自引:0,他引:6
Andreas Mackensen Thomas Krause Uli Blum Peter Uhrmeister Roland Mertelsmann Albrecht Lindemann 《Cancer immunology, immunotherapy : CII》1999,48(2-3):118-122
Dendritic cells (DC) are professional antigen-presenting cells that can be generated in vitro from CD34+ peripheral blood progenitor cells by recombinant cytokines. These cells have potential implications for immunotherapeutic
approaches in the treatment of cancer and other diseases. Physiologically, immature DC in the periphery capture and process
antigens, then mature to interdigitating DC and migrate to lymphoid organs, where they activate lymphocytes. However, it is
not known if DC generated in vitro have the capacity to traffic in vivo to the lymphoid tissues, such as spleen and lymph
nodes. We have investigated whether human radiolabeled DC differentiated in vitro migrate and localize to lymphoid tissues
after intravenous and intralymphatic injection. The distribution and localization of the DC were evaluated in five patients
with malignant melanoma using serial whole-body gamma camera imaging. Intravenously infused DC demonstrated transient lung
uptake followed by localization in the spleen and liver for at least 7 days. DC injected into a lymphatic vessel at the dorsal
foot were rapidly detected in the draining lymph nodes where they remained for more than 24 h. These data suggest that DC
differentiated in vitro localize preferentially to lymphoid tissue, where they could induce specific immune responses.
Received: 28 January 1999 / Accepted: 4 March 1999 相似文献
7.
Ribas A Vo DD Weeks DL Comin-Anduix B Schumacher LY Garban HJ McLean C Yang J Dissette VB Peraza P Owens SK McBride WH Glaspy JA Economou JS 《Cancer immunology, immunotherapy : CII》2006,55(6):663-671
Dendritic cell (DC) administration to CD8α knock-out (CD8αKO) mice results in a strong antigen-non-specific protection to
a B16 murine melanoma tumor challenge. This response is mediated by lytic NK cells and cytokine-producing CD4 cells. We aimed
to determine the signals that guide tumor targeting of this response. CD8αKO mice in the C57BL/6 background received subcutaneous
(s.c.) injections of immature DC. Mice were challenged in vivo or assayed for lytic activity in vitro to a panel of syngeneic
tumors with different levels of MHC class I expression. These studies support the following conclusions: (1) DC administration
to CD8αKO mice results in protective in vivo responses to syngeneic tumors from epithelial, neuroectodermal and hematopoietic
origin; in vivo protection is independent of the level of MHC classes I and II expression. (2) The in vitro lytic activity
of DC-activated NK cells from CD8αKO mice has sensitive and insensitive targets, which is independent of the cell lineage
or the level of inhibitory self-MHC surface molecules. (3) In sensitive targets a putative activating NK ligand in DC-stimulated
NK cells from CD8αKO mice signals directly to PI3-K, but is distinct from NKG2D. 相似文献
8.
Dominique Pinard N.-O. Olsson William H. Chambers François Martin 《Cancer immunology, immunotherapy : CII》1996,42(1):15-23
NKR-P1 has been identified as a triggering structure selectively expressed on rat natural killer (NK) cells and adherent
lymphokine-activated killer (A-LAK) cells. In vivo treatment with anti-NKR-P1 monoclonal antibody (mAb 3.2.3) was shown to
induce complete inhibition of NK cytotoxicity and elimination of LAK cell precursors in Lewis and Fisher rat strains. We investigated
the effects of mAb 3.2.3 in a colon tumor model in BDIX rats. Inoculation of animals with mAb 3.2.3 even at very high doses
induced a strong but incomplete inhibition of NK cytotoxicity in nylon-wool-non-adherent spleen and peripheral blood cells.
Generation of adherent A-LAK cells from their spleen precursors was also strongly but not fully inhibited. We also investigated
the effect of treatment with mAb 3.2.3 on the tumorigenicity of the NK-sensitive REGb cell line. When subcutaneously inoculated
in syngeneic animals, REGb cells induce tumors that first grow for 2 weeks, then spontaneously regress and disappear. In contrast
with previous results using anti-asialoGM1, no significant difference in tumor growth was observed between rats treated with
mAb 3.2.3 and control animals, even with a long-term treatment. In vitro, mAb 3.2.3 exhibited the same incomplete efficiency.
Nylon-wool-non-adherent spleen cells treated with mAb 3.2.3 plus complement were completely free of 3.2.3bright cells, but retained a substantial NK activity and generated LAK cells after culture with IL-2. After an overnight incubation
in standard medium of 3.2.3-depleted spleen cells, 3.2.3bright cells were partially recovered and the NK cytotoxic activity, as well as the generation of LAK cells, was significantly enhanced.
These results suggest that a strong expression of NKR-P1 is not required for BDIX mononuclear cells to exhibit NK function
and generate LAK cells under IL-2 activation.
Received: 11 July 1995 / Accepted: 16 November 1995 相似文献
9.
Huck SP Tang SC Andrew KA Yang J Harper JL Ronchese F 《Cancer immunology, immunotherapy : CII》2008,57(1):63-71
Aims
To examine the effects of route of administration and activation status on the ability of dendritic cells (DC) to accumulate in secondary lymphoid organs, and induce expansion of CD8+ T cells and anti-tumor activity.Methods
DC from bone marrow (BM) cultures were labeled with fluorochromes and injected s.c. or i.v. into naïve mice to monitor their survival and accumulation in vivo. Percentages of specific CD8+ T cells in blood and delayed tumor growth were used as readouts of the immune response induced by DC immunization.Results
The route of DC administration was critical in determining the site of DC accumulation and time of DC persistence in vivo. DC injected s.c. accumulated in the draining lymph node, and DC injected i.v. in the spleen. DC appeared in the lymph node by 24 h after s.c. injection, their numbers peaked at 48 h and declined at 96 h. DC that had spontaneously matured in vitro were better able to migrate compared to immature DC. DC were found in the spleen at 3 h and 24 h after i.v. injection, but their numbers were low and declined by 48 h. Depending on the tumor cell line used, DC injected s.c. were as effective or more effective than DC injected i.v. at inducing anti-tumor responses. Pre-treatment with LPS increased DC accumulation in lymph nodes, but had no detectable effect on accumulation in the spleen. Pre-treatment with LPS also improved the ability of DC to induce CD8+ T cell expansion and anti-tumor responses, regardless of the route of DC administration.Conclusions
Injection route and activation by LPS independently determine the ability of DC to activate tumor-specific CD8+ T cells in vivo.10.
Bone marrow cells cultured for 5-6 days generate cytotoxic activity against a number of natural killer (NK)-susceptible tumor cells. In this study, these bone marrow cytotoxic cells were compared to cells with NK activity obtained either from spleen cells activated in vitro with interferon (IFN-alpha/beta) or mitogen or from peritoneal exudate cells (PEC) obtained 4 days after bacillus Calmette-Guerin (BCG) infection. Splenic and PEC cytotoxic cells were shown to be Thy 1.2+, NK 1.1+, Asialo GM+1, Lyt 1.2-, Lyt 2.2-. In contrast, bone marrow cytotoxic cells were Thy 1.2+, NK 1.1-, Lyt 1.2-, Lyt 2.2- and expressed low levels of Asialo GM1 antigen (Asialo GM +/- 1). Precursor cells for bone marrow cytotoxic activity were shown to be Thy 1.2-, NK 1.1-, Lyt 1.2-, Lyt 2.2- but also expressed low levels of Asialo GM1 antigen (Asialo GM +/- 1). Cytotoxic activity for both bone marrow and spleen cells peaked in the low-density fractions of discontinuous Percoll density gradients. The cytotoxic activity of these bone marrow cells was augmented by pretreatment with IFN (-alpha/beta, -gamma) or soluble factors (IFN free) from activated EL-4 thymoma cells. Surprisingly, the ability of bone marrow cells to generate high levels of cytotoxic activity following in vitro culture appeared to be associated primarily with mice which were of the H-2b haplotype. 相似文献
11.
Diao J Winter E Cantin C Chen W Xu L Kelvin D Phillips J Cattral MS 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(12):7196-7206
The developmental biology of dendritic cells (DC) under physiological conditions remains unclear. In this study, we show that mouse CD11c(+) MHC class II(-)lineage(-) cells are immediate precursors of conventional DC and are widely distributed in both bone marrow and lymphoid tissues. These precursors have a high clonal efficiency, and when cocultured on a supportive stromal monolayer or adoptively transferred in vivo, generate a population CD11c(+)MHC class II(+) DC that retain limited proliferation capacity. During steady state conditions, a small proportion of immediate DC precursors (DCp) and DCs are dividing actively in bone marrow and spleen. Cytokines that initiate and support proliferation of immediate DCp were defined. Collectively, our findings provide evidence of a distinct development pathway for conventional DC in both bone marrow and lymphoid tissues and highlight the importance of in situ replication of immediate DCp and DC in maintaining conventional DC populations. 相似文献
12.
Allogeneic gastric cancer cell-dendritic cell hybrids induce tumor antigen (carcinoembryonic antigen) specific CD8+ T cells 总被引:3,自引:0,他引:3
Matsumoto S Saito H Tsujitani S Ikeguchi M 《Cancer immunology, immunotherapy : CII》2006,55(2):131-139
The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research of their potential
use in immunotherapy. Accumulating results show the efficacy of this treatment on melanomas which are highly immunogenic.
However, its efficacy remains unclear in other tumors. In this study, allogeneic gastric cancer cell–DC hybrids were used
to determine the efficacy of this type of immunotherapy in gastric cancer. Fusion cells of DC and allogeneic gastric cancer
cells were generated by polyethylene glycol (PEG) and electrofusion. These hybrids were used to induce tumor associated antigen
(TAA) specific cytotoxic T lymphocytes (CTLs). The DCs were successfully fused with the allogeneic gastric cancer cells resulting
in hybrid cells. These hybrid cells were functional as antigen-presenting cell because they induced allogeneic CD4+ T cells
proliferation. CD8+ T cells stimulated by the MKN-45-DC hybrid cells were able to kill MKN-45 when used for immunization.
The CTLs killed another gastric cancer cell line, MKN-1, as well as a melanoma cell line, 888mel, suggesting the recognition
of a shared tumor antigen. MKN-45 specific CTLs can recognize carcinoembryonic antigen (CEA), indicating that the killing
is due to tumor antigens as well as alloantigens. This approach suggests the possible use of allogeneic gastric cancer cell–DC
hybrids in DC based immunotherapy for gastric cancer treatment. 相似文献
13.
Yu S Liu C Su K Wang J Liu Y Zhang L Li C Cong Y Kimberly R Grizzle WE Falkson C Zhang HG 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(11):6867-6875
The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. In this study, we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b(+) myeloid precursors in the bone marrow (BM) in vivo, and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block the differentiation of murine myeloid precursor cells into dendritic cells (DC) in vitro. Addition of tumor exosomes at day 0 led to a significant block of differentiation into DC, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited the differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after the tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of BM cells isolated from IL-6 knockout mice. Addition of a rIL-6 to the IL-6 knockout BM cell culture restored the tumor exosome-mediated inhibition of DC differentiation. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking BM DC differentiation. 相似文献
14.
Innate direct anticancer effector function of human immature dendritic cells. I. Involvement of an apoptosis-inducing pathway 总被引:3,自引:0,他引:3
Janjic BM Lu G Pimenov A Whiteside TL Storkus WJ Vujanovic NL 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(4):1823-1830
Dendritic cells (DCs) mediate cross-priming of tumor-specific T cells by acquiring tumor Ags from dead cancer cells. The process of cross-priming would be most economical and efficient if DCs also induce death of cancer cells. In this study, we demonstrate that normal human in vitro generated immature DCs consistently and efficiently induce apoptosis in cancer cell lines, freshly isolated noncultured cancer cells, and normal proliferating endothelial cells, but not in most normal cells. In addition, in vivo generated noncultured peripheral blood immature DCs mediate similar tumoricidal activity as their in vitro counterpart, indicating that this DC activity might be biologically relevant. In contrast to immature DCs, freshly isolated monocytes (myeloid DC precursors) and in vitro generated mature DCs are not cytotoxic or are less cytotoxic, respectively, suggesting that DC-mediated killing of cancer cells is developmentally regulated. Comparable cytotoxic activity is mediated by untreated DCs, paraformaldehyde-fixed DCs, and soluble products of DCs, and is destructible by proteases, indicating that both cell membrane-bound and secreted proteins mediate this DC function. Overall, our data demonstrate that human immature DCs are capable of inducing apoptosis in cancer cells and thus to both directly mediate anticancer activity and initiate processing of cellular tumor Ags. 相似文献
15.
We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype
(Id)-specific CD8+ cytotoxic T lymphocytes (CTL) are generated in mice following hyperimmunization with irradiated tumor cells, and that they
are effective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor
progression, but are not sustained. At the early stage of tumor growth, the splenic T cells following a 5-day incubation in
vitro with killed 2C3 tumor targets, produce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon γ
(IFNγ). Their cytotoxic T lymphocyte (CTL) activity and cytokine levels, except IL-2, sharply decline at the late stage when
the mice are increasingly moribund. Although the decline in cytokine level is also evident with CD4+ T cells, a precipitous and concurrent decrease occurs primarily in the IL-4 level with both CD4+ and CD8+ T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4
is produced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition
of supernatants from the splenocyte culture of early TBA, or by IL-4, but not by IFNγ and IL-10. In addition, only IL-4-activated
CD8+ T cells from the late TBA are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain
antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising
host immunity against the tumor. We contend that induction or maintenance of protective immunity depends not only on the tumor
antigen but also on the specific cytokine milieu in a tumor-bearing host.
Received: 8 February 1997 / Accepted: 24 April 1997 相似文献
16.
Efficient induction of antitumor cytoxic T lymphocytes from a healthy donor using HLA-A2-restricted MAGE-3 peptide in vitro 总被引:1,自引:0,他引:1
F. Tanaka Tatsuo Fujie Hiroki Go Kinya Baba Masaki Mori Kazutoh Takesako Tsuyoshi Akiyoshi 《Cancer immunology, immunotherapy : CII》1997,44(1):21-26
The antigenic peptides encoded by tumor-rejection antigen genes, MAGE-1 and -3, have been identified, and various methods have been utilized for the in vitro induction of MAGE-specific, cytotoxic
T lymphocytes (CTL) from peripheral blood mononuclear cells (PBMC) using synthetic peptides. However, all of these methods
are technically demanding and thus have a relatively limited usefulness. We herein report a simple and efficient method for
the in vitro induction of specific CTL by using the HLA-A2-restricted MAGE-3 peptide from the PBMC of a healthy donor. CTL
responses could thus be efficiently induced from unseparated PBMC by stimulation with freshly isolated, peptide-pulsed PBMC
as antigen-presenting cells and by using interleukin-7 and keyhole limpet hemocyanin for the primary culture. The induced
CTL could thus recognize and lyse not only HLA-A2 target cells pulsed with the peptide but also HLA-A2 tumor cells expressing
MAGE-3, in an HLA-class-I-restricted manner. This simple method may, therefore, become a useful tool for investigating the
potential peptides for tumor antigens as well as for developing various immunotherapeutic approaches for human malignant tumors.
Received: 15 October 1996 / Accepted: 6 December 1996 相似文献
17.
Veto cell-mediated suppression of CTL responses has been proposed as one mechanism by which self tolerance is maintained in mature T cell populations. We have reported that murine bone marrow cells cultured in the presence of high-dose IL-2 (activated bone marrow cells) mediate strong veto suppressor function in vitro and in vivo, and that such veto activity is effected through clonal deletion of cytotoxic T cell precursors. In our studies, we have determined that bone marrow cell populations from athymic NCr-nu mice (H-2d) mediate strong veto cell activity without exposure to exogenous IL-2 in vitro. To examine mechanisms by which these naturally occurring veto cell populations in BM suppress precursor CTL (pCTL) responses, we used as a responding cell population in MLC, spleen cells of transgenic mice expressing at high frequency TCR specific for H-2 Ld encoded Ag with stimulation by H-2d-expressing cells in culture. Flow cytometric analysis was performed by staining the responding MLC cell population with the mAb 1B2 specific for the transgene-encoded TCR and determined changes of 1B2+ T cells. Such experiments demonstrated that the anti-H-2d cytotoxic response by these cell populations was specifically suppressed by NCr-nu (H-2d) bone marrow, and that 1B2+ pCTL were in fact specifically deleted from the responding cell population by incubation with such naturally occurring veto cell populations expressing the appropriate target Ag. In addition, to further understand the interactions of pCTL and veto cells and possible contributions by the latter to peripheral tolerance, we evaluated the effect of cyclosporine A (CsA) on veto cell-mediated suppression of pCTL of the transgenic mice. CsA inhibited veto cell-mediated suppression of cytotoxic T cell responses, and this inhibition correlated with a lack of clonal deletion of pCTL by veto cells in the presence of CsA. Furthermore, CsA exerted its effect through pCTL and not through veto cells, indicating that pCTL may play an active role in their own deletion by veto cells. 相似文献
18.
M. Margaret Prechel Yvonne Lozano Mark A. Wright J. Ihm M. R. I. Young 《Cancer immunology, immunotherapy : CII》1996,42(4):213-220
Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor
cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal
immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow
for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3 eliminated natural suppressor activity. In mice that were first treated with vitamin D3 and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus
IL-2. In addition, spleen and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although
IL-2 production was not stimulated. A prominent effect of the combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional
lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity
was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show
that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production
and cytolysis by regional lymph node cells of autologous tumor.
Received: 15 December 1995 / Accepted: 22 March 1996 相似文献
19.
The NV epitope, a dominant helper determinant from the circumsporozoite antigen of Plasmodium falciparum, is strongly immunogenic and can provide help for cytotoxic T-lymphocyte (CTL) activation. In this study, we evaluated whether the addition of NV peptide can augment the efficacy of peptide-pulsed dendritic cell (DC) immunization in vivo. Using B16 melanoma as tumor model, we demonstrated that DCs pulsed with both NV and gp100 (a melanoma-specific antigen) peptide enhanced immune priming and protection from tumor challenge in vivo. Further, we showed the mechanisms of the NV epitope that help CTL activation; MHC-II-restricted NV peptide induced dramatically more effective helper cells, with a higher level of CD40L expression and IFN-γ production, which, in turn, more effectively conditioned DCs for CTL activation. The improved helper cells also induced greater IL-12 production by DCs, accounting for the reciprocal T-helper polarization to Th1, and increased the expression of costimulatory molecules. Collectively, these findings demonstrate that NV peptide in addition to tumor antigen-pulsed DC immunizations augment helper cell activation, which in turn promotes maturation of DC, and enhance in vivo antitumor activity. 相似文献
20.
Stimulation of immune suppressive CD34+ cells from normal bone marrow by Lewis lung carcinoma tumors
Mark A. Wright Kristina Wiers Kishore Vellody Dragana Djordjevic M. Rita I. Young 《Cancer immunology, immunotherapy : CII》1998,46(5):253-260
Progressive growth of metastatic Lewis lung carcinoma (LLC-LN7) tumors is associated with increased levels of bone-marrow-derived
CD34+ cells having natural suppressor (NS) activity toward T cells. The present studies determined whether tumor-derived products
are responsible for this induction of NS activity. Culturing normal bone marrow cells with LLC-LN7-conditioned medium (LLC-CM)
or with recombinant granulocyte/macrophage-colony-stimulating factor (GM-CSF) resulted in the appearance of NS activity. The
development of NS activity coincided with a prominent increase in the levels of CD34+ cells. That the CD34+ cells were responsible for the NS activity of the bone marrow cultures containing LLC-CM was shown by the loss of NS activity
when CD34+ cells were depleted. The stimulation of CD34+ NS cells by LLC-CM was attributed to tumor production of GM-CSF, since neutralization of GM-CSF within the LLC-CM reduced
its capacity to increase CD34+ cell levels. Studies also showed that the induction of CD34+ NS cells by LLC-CM and GM-CSF could be overcome by including in the cultures an inducer of myeloid differentiation, 1α,25-dihydroxyvitamin
D3 [1,25(OH)2D3]. These results demonstrate that the mechanism by which the LLC-LN7 tumors stimulate increased levels of CD34+ NS cells from normal bone marrow is by their production of GM-CSF and that this can be blocked with the myeloid differentiation
inducer 1,25(OH)2D3.
Received: 8 December 1997 / Accepted: 27 February 1998 相似文献