共查询到20条相似文献,搜索用时 15 毫秒
1.
Michael G. Rosenblum Lawrence Cheung Kalpana Mujoo James L. Murray 《Cancer immunology, immunotherapy : CII》1995,40(5):322-328
The ability of monoclonal antibody conjugates to re-direct plant or bacterial toxins, chemotherapeutic agents and radionuclides to selected target cells has been well-documented. Recombinant human tumor necrosis factor (TNF) is a macrophage-derived, non-glycosylated (17 kDa) peptide with a broad range of biological and immunological effects including antiviral activity, cytotoxic and cytostatic effects. A conjugate of the antimelanoma antibody ZME-018 and TNF in previous studies has shown melanoma-selective cytotoxic effects in vitro. Pharmacokinetic studies of the ZME-TNF immunotoxin showed that the agent cleared from plasma biphasically with -and -phase half-lives similar to that of ZME itself (72 min and 36 h compared to 84 min and 41 h respectively). In contrast, TNF itself was cleared rapidly from plasma with a terminalphase half-life of only 2.7 h. The clearance rate of ZME-TNF from plasma (Clp) was almost tenfold more rapid than for ZME (1.1 versus 0.16 ml/kg x min) but was threefold slower than the clearance for TNF itself (3.4 ml/kg x min). Tissue distribution studies in nude mice bearing human melanoma xenografts showed similar tumor localization of the immunotoxin compared to the free antibody and slightly higher concentrations in liver and kidney compared to ZME itself. Treatment of nude mice bearing well-developed A375 tumors with the immunotoxin resulted in a statistically significant (P<0.002) suppression in tumor growth rate (fivefold increase) compared to saline-treated controls, which increased 20-fold over the same period. These studies demonstrate the feasibility of this approach and suggest that TNF may represent a non-antigenic alternative to immunotoxins containing plant and bacterial toxins.Research conducted, in part, by the Clayton Foundation for Research 相似文献
2.
Cellular immune responses to autologous chronic myelogenous leukaemia cells in vitro 总被引:2,自引:0,他引:2
Graham Pawelec Arnika Rehbein Elke Schlotz Paul da Silva 《Cancer immunology, immunotherapy : CII》1996,42(3):193-199
Using a modification of the autologous mixed lymphocyte/tumour cell culture (MLTC), it is demonstrated here that lymphocytes
from chronic-phase myelogenous leukaemia (CML) patients (n = 58), but not from their HLA-identical siblings, proliferated upon coculture with autologous tumour cells. However, in most
cases, the level of proliferation measured was low (stimulation index <3, n = 37). This was most likely related to the amount of interleukin-10 (IL-10) released into the culture medium by the CML cells,
because addition of neutralizing anti-IL-10 serum to MLTC markedly enhanced proliferative responses. In addition, supplementation
of media with IL-1α further enhanced proliferative responses and a combination of anti-IL-10 serum and IL-1α was more effective
than either agent alone. Only HLA-DR-matched CML cells, but not HLA-DR-mismatched CML cells or matched or mismatched PBMC
restimulated proliferation of IL-2-dependent T cell lines derived from MLTC supplemented with IL-1α and anti-IL-10 serum.
The responding cells under these conditions were predominantly CD4+ and secreted IL-2, and interferon γ; some secreted IL-4, but none secreted IL-10. These data therefore suggest the existence
of an HLA-DR-restricted DTH/Th1-type of tumour-specific immunity in CML patients, which may be down-regulated in vitro by
excessive secretion of IL-10 together with depressed secretion of IL-1.
Received: 9 November 1995 / Accepted: 8 February 1996 相似文献
3.
Immunization of mice with melanoma cells transfected to secrete the superantigen, staphylococcal enterotoxin A 总被引:8,自引:0,他引:8
David P. Shrayer Nicolas Kouttab Vincent J. Hearing Harold J. Wanebo 《Cancer immunology, immunotherapy : CII》1998,46(1):7-13
Immunization of mice with a melanoma vaccine coupled with staphylococcal enterotoxin A (SEA) inhibits the growth of primary melanoma tumors in mice. We have now successfully transfected B16 cells with the sea gene and have immunized C57BL/6 mice subcutaneously once per week for 4 weeks prior to tumor challenge with vaccines of irradiated B16 cells or, 4 weeks following tumor challenge of naïve mice with B16 cells, with irradiated B16 cells transfected with the sea gene. Primary tumor growth following both types of treatments was inhibited significantly. To characterize immune responses to these immunogens, we examined the production of antibodies to the B700 melanoma antigen, the stimulation of endogenous IL-2 production, the expression of CD4, CD8, Vβ and CD25 T cell markers, and the induction of NK activity. At 4 weeks following immunization of mice, there was a significant increase (P<0.05) in levels of interleukin-2 production by splenocytes from mice immunized with SEA-secreting B16 cells or with the parental B16 cells, compared to controls. Levels of antibodies to the B700 melanoma antigen were also significantly higher in mice immunized with the SEA-secreting B16 cells, as was expression of CD4, CD8, CD25 and Vβ T cell antigens, particularly CD4. Natural killer cell activity (at various E:T ratios) was tenfold higher in splenocytes of mice immunized with SEA-secreting B16 cells, and fivefold higher in mice immunized with the parental B16 cells, compared to controls.?These data confirm the possibility of using irradiated murine melanoma cells transfected to secrete SEA in vaccines targeted at preventing the development and growth of melanoma. 相似文献
4.
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
5.
N. Mador Haya Falk Michael Bergel Amos Panet J. Hochman 《Cancer immunology, immunotherapy : CII》1997,44(5):249-256
We have previously developed an experimental model for the xenogenization of malignant lymphoma. From highly tumorigenic
S49 mouse lymphoma cells that proliferate in suspension culture (designated T-25), we selected variant clones that grew as
an adherent monolayer (designated T-25-Adh) and were non-tumorigenic in syngeneic mice. Furthermore, priming of syngeneic
hosts with T-25-Adh cells protected them against subsequent challenges with the tumorigenic T-25 cells. Several lines of evidence
have indicated that antigens of an endogenous mouse mammary tumor virus (MMTV) are involved in the immunogenicity of T-25-Adh
cells. Since interferon (IFN) is known to affect retroviral assembly and maturation on the cell membrane, we have studied
the effects of IFN on endogenous MMTV-related structures, as well as on the immunogenicity of T-25-Adh cells. We observed
that mouse α and β interferons affect the morphogenesis of intracellular MMTV-related precursors in the immunogenic T-25-Adh
cells, but not in tumorigenic T-25 cells. From T-25-Adh cells we selected variants that were either high responders or low
responders to the above-mentioned interferon effect. The high-response variants were significantly more protective against
tumorigenic T-25 cells than the low-response variants. Involvement of MMTV-related antigens in the immune response of the
host to T-25-Adh cells was further suggested by immunoelectron-microscopical analysis, demonstrating that antisera from mice,
immunized with T-25-Adh cells, interacted specifically with cell-surface MMTV budding particles. These findings indicate a
novel method for xenogenization of lymphoma cells by IFN. Since endogenous retroviruses are present in all tissues of the
mouse, this approach might be applicable to a wide variety of tumors.
Received: 6 June 1995 / Accepted: 13 March 1997 相似文献
6.
A.-D. Le Lann-Terrisse Gilbert Jean Fournié Hervé Benoist 《Cancer immunology, immunotherapy : CII》1997,43(6):337-344
Our previous data suggested that chromatin fragments released from dead cells into the extracellular medium could be involved
in the impairment of natural-killer (NK)-mediated cytotoxicity reported in cancer patients. In the present study, an inhibition
of the NK-mediated lysis was obtained in vitro by nucleosome addition to different tumor target cells, independently of their
sensitivity to NK-mediated lysis. We observed a rapid endocytosis and degradation of nucleosomes by K562 tumor target cells
and (although to a much lesser extent) a binding to a subpopulation of lymphocytes. Nucleosomes impaired neither the conjugation
step nor the expression of adhesion molecules at the effector (CD11a, CD18, CD2) or target (CD54, CD58) cell surface. On the
contrary, flow-cytometry analysis of the conjugation suggested that nucleosomes might stabilize the conjugates. Investigations
of the killing process showed that nucleosomes decreased the NK cytotoxic potential without modifying Ca2+-dependent lethal-hit-delivery kinetics. The cytotoxic potential was not restored by increasing the available magnesium and
calcium concentrations in the extracellular medium. Taken together, the results suggest that the inhibition of NK-mediated
lysis by nucleosomes may result from alterations of the NK mechanism at the postconjugation level and after lethal-hit delivery.
Hence, the inhibition could involve a delay in the recycling of effector cells, or a resistance of tumor target cells to NK
cells.
Received: 7 October 1996 / Accepted: 12 November 1996 相似文献
7.
Alexei F. Kirkin P. thor Straten J. Zeuthen 《Cancer immunology, immunotherapy : CII》1996,42(4):203-212
Human melanoma is a highly immunogenic tumor capable of inducing a specific immune response. A number of melanoma-associated
antigens have been characterized during the past several years and can be classified into two groups: differentiation antigens
– present also in normal melanocytes – and tumor-specific antigens, which, with the exception of testis, are present only
in tumor cells. In a previous publication [Kirkin A. F., Petersen T. R., Olsen A. C., Li L., thor Straten P., Zeuthen J. (1995)
Cancer Immunol Immunother 41:71] we have described the production of clones of cytotoxic T lymphocytes (CTL) against the highly
immunogenic human melanoma cell line FM3. Using these clones we have defined four previously unknown melanoma-associated antigens,
which could be subdivided into differentiation and progression antigens. In the experiments reported in this paper, we have
further compared CTL clones from different groups and shown that the sensitivity of melanoma cells to CTL that recognize differentiation
or progression antigens is differentially modulated during tumor progression as well as by the lymphokines interferon γ (IFNγ)
and interleukin-10 (IL-10). The interaction of CTL clones recognizing progression antigens was strongly increased after treatment
of melanoma cells with IFNγ, while the recognition by CTL clones specific for differentiation antigens either was unchanged
or significantly decreased. IL-10 treatment of melanoma cells induced up-regulation with respect to recognition by CTL clones
specific for differentiation antigens without affecting the recognition of melanoma cells by CTL clones specific for progression
antigens. Using cellular systems at different stages of tumor progression, we demonstrated that the progressed state of melanoma
cells is associated with increased sensitivity to recognition by CTL clones detecting progression antigens, and with decreased
sensitivity to CTL clones recognizing differentiation antigens. Mimicking tumor progression, treatment with IFN-γ induced
apparent down-regulation of differentiation antigens. A hypothesis is suggested in which IFN-γ plays different roles in the
immune response against poorly immunogenic and highly immunogenic melanoma cells, increasing the progression of poorly immunogenic
tumor cells or promoting a strong immune response and regression of highly immunogenic melanoma cells.
Received: 23 November 1995 / Accepted: 7 March 1996 相似文献
8.
Weisong Xu Edwin de Zoeten Victoria Carr-Brendel E. P. Cohen 《Cancer immunology, immunotherapy : CII》1997,45(5):217-224
Tumor-associated T cell epitopes are recognized by T cells in the context of determinants specified by class I loci. Since
the rejection of foreign histocompatibility antigens is known to enhance tumor immunity, immunization with a cellular vaccine
that combined the expression of both syngeneic and allogeneic class I determinants could have important immunological advantages
over a vaccine that expressed either syngeneic or allogeneic determinants alone. To investigate this question in a mouse melanoma
model system, we tested the immunotherapeutic properties of B16 melanoma × LM fibroblast hybrid cells in C57BL/6J mice with
melanoma. Like C57BL/6J mice, B16 cells expressed H-2Kb class I determinants and (antibody-defined) melanoma-associated antigens. LM cells, of C3H mouse origin, formed H-2Kk determinants along with B7.1, a co-stimulatory molecule that can activate T cells. The B16 × LM hybrid cells co-expressed
H-2Kb and H-2Kk class I determinants, B7.1 and the melanoma-associated antigens. C57BL/6J mice with melanoma, immunized with the semi-allogeneic
hybrid cells, developed CD8-mediated melanoma immunity and survived significantly (P<0.005) longer than mice with melanoma
immunized with a mixture of the parental cell types. The failure of melanoma immunity to develop in mice injected with the
mixture of parental cells indicated that co-expression of the immunogenic determinants by the same cellular immunogen was
necessary for an optimum immunotherapeutic effect. Augmented immunity to melanoma in mice immunized with the semi-allogeneic
hybrid cells points toward an analogous form of therapy for patients with melanoma.
Received: 19 May 1997 / Accepted: 23 July 1997 相似文献
9.
Seedling growth strategies and seed size effects in fourteen oak species native to different soil moisture habitats 总被引:12,自引:0,他引:12
Seedling growth and morphology are thought to reflect evolutionary responses to habitat or influences of seed size. To test
these hypotheses, we selected fourteen species of North American oaks differing in soil moisture habitat preference and seed
size. Seedlings were grown for 1 – 2 years with abundant soil water and moderate soil nutrition in pots placed outdoors and
in a common garden. Oak species native to xeric environments produced the smallest seedlings. Oaks from hydric soils had more
shoot weight per unit of root weight and more height per unit of total plant weight than did mesic or xeric oaks. Essentially
no differences in leaf area per unit of total plant weight were detected. Species with thinner and larger individual leaves
tended to produce larger seedlings. Within species, seed size was generally unrelated to seedling growth, although results
may have been complicated by uncontrolled genotypic variability. However, when species were compared, those with larger mean
seed size produced larger seedlings. Root/shoot allometry, height growth and leaf thickness in the tested species may reflect
evolutionary responses to soil moisture and flooding. Although seed size influenced seedling growth, no clear relationship
between seed size and soil moisture habitat was found.
Received: 26 March 1995 / Accepted: 30 November 1995 相似文献
10.
C. Renner Gerhard Held Sascha Ohnesorge Stefan Bauer Klaus Gerlach Jan-Peter Pfitzenmeier Michael Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,44(2):70-76
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes,
induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis
contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation,
FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for
perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity
in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative
state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance
of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells
in bi-mAb-mediated apoptosis and necrosis of tumor cells.
Received: 5 December 1996 / Accepted: 16 January 1997 相似文献
11.
Tamaria G. Dewdney Yong Wang Zhigang Liu Shiv K. Sharma Samuel J. Reiter Joseph S. Brunzelle Iulia A. Kovari Patrick M. Woster Ladislau C. Kovari 《Bioorganic & medicinal chemistry》2013,21(23):7430-7434
Proper proteolytic processing of the HIV-1 Gag/Pol polyprotein is required for HIV infection and viral replication. This feature has made HIV-1 protease an attractive target for antiretroviral drug design for the treatment of HIV-1 infected patients. To examine the role of the P1 and P1′positions of the substrate in inhibitory efficacy of multi-drug resistant HIV-1 protease 769 (MDR 769), we performed a series of structure–function studies. Using the original CA/p2 cleavage site sequence, we generated heptapeptides containing one reduced peptide bond with an L to F and A to F double mutation at P1 and P1′ (F-r-F), and an A to F at P1′ (L-r-F) resulting in P1/P1′ modified ligands. Here, we present an analysis of co-crystal structures of CA/p2 F-r-F, and CA/p2 L-r-F in complex with MDR 769. To examine conformational changes in the complex structure, molecular dynamic (MD) simulations were performed with MDR769–ligand complexes. MD trajectories show the isobutyl group of both the lopinavir analog and the CA/p2 L-r-F substrate cause a conformational change of in the active site of MDR 769. IC50 measurements suggest the non identical P1/P1′ ligands (CA/p2 L-r-F and lopinavir analog) are more effective against MDR proteases as opposed to identical P1/P1′ligands. Our results suggest that a non identical P1/P1′composition may be more favorable for the inhibition of MDR 769 as they induce conformational changes in the active site of the enzyme resulting in disruption of the two-fold symmetry of the protease, thus, stabilizing the inhibitor in the active site. 相似文献
12.
Magnus Essand P. Lögdahl Sten Nilsson Maria Wartenberg Helmut Acker J. Carlsson 《Cancer immunology, immunotherapy : CII》1996,43(1):39-43
Cellular retention and processing of a radiolabelled monoclonal anti-prostate antibody were evaluated after binding to prostatic
adenocarcinoma DU 145 cells. An endocytosis assay revealed that the rate of release of radioactivity from the cells had an
initially rapid phase within the first hours after antibody incubation, which was presumably due to release of monovalently
bound antibodies. This was followed by a slower phase, with the possible release of intact bivalently bound antibodies and
excretion of degraded internalized antibodies. The relative amount of released radioactivity of high molecular mass was high,
indicating that the major part of the antibodies were released without being internalized and degraded. However, when only
the radiolabelled antibody that remained cell-associated after 2 h and longer was considered, a substantial part was found
to be internalized and radioactive degradation products were excreted. About 30% of the initially cell-associated radioactivity
still remained associated with the cells after 48 h, indicating a rather slow antibody processing, which is favourable if
the antibody is to be used for targeted radiotherapy. The retention of cell-associated radioiodine was very similar irrespective
of whether the antibodies were radiolabelled with the direct chloramine-T method or the indirect ATE (succinimidyl based reagent)
method. Since the ATE method can be used to form stable antibody constructs with the therapeutically relevant alpha-emitting
radionuclide, astatine-211, this was an interesting finding that will be further evaluated in the future.
Received: 20 March 1996 / Accepted: 25 June 1996 相似文献
13.
14.
Heike K. E. Boxhorn Jason G. Smith Yueh J. Chang DuPont Guerry William M. F. Lee Ulrich Rodeck Laurence A. Turka Stephen L. Eck 《Cancer immunology, immunotherapy : CII》1998,46(5):283-292
Previous studies in experimental models have demonstrated that the transduction of human or murine melanoma cells with the
co-stimulatory B7-1 molecule induces effective antitumor immune responses. In order to develop B7-1 gene transfer as a therapeutic
tool in the clinical management of melanoma, efficient means of in vivo gene transfer must be used. To this end we evaluated
in vitro and in vivo immune responses associated with adenoviral transduction of murine and human melanoma cells with B7-1.
Adenovirus-mediated transduction of human and murine melanoma cells with B7-1 leads to high-level transgene expression in
vitro and in vivo and does not affect MHC class I and II expression. Adenovirus-delivered B7-1 induced antitumor immune responses,
on the basis of observations that human melanoma cells transduced to express human B7-1 were able to co-stimulate allogeneic
and autologous T cells to proliferate and that murine melanoma K1735 cells transduced to express murine B7-1 were rejected
by syngeneic, immunocompetent mice. By contrast, intratumoral injection of an adenovirus encoding murine B7-1 failed to eliminate
established murine melanoma (K1735) despite high-level transgene expression in tumor cells. Potent T cell inhibitory factor(s)
secreted by both K1735 cells and select human melanoma cells may contribute to the failure to achieve protection in this setting.
Thus, immune inhibitory melanoma-derived factors need to be taken into account when considering the clinical use of B7-1 immunotherapy.
Received: 21 December 1997 / Accepted: 16 March 1998 相似文献
15.
16.
目的检测多重耐药伤寒沙门菌对抗菌药物的敏感性及其耐药基因携带情况,为伤寒沙门菌引起的腹泻治疗提供科学依据。方法采用微量肉汤稀释的方法测定大连地区临床分离的78株伤寒沙门菌对12种抗生素的敏感性;用PCR方法检测TEM型β内酰胺酶基因、catA和catB氯霉素乙酰基转移酶基因以及cmlA氯霉素外排泵蛋白基因、aac(6′)Ⅰb和aac3Ⅱ型氨基糖苷类修饰酶基因、qacEΔ1sul1耐消毒剂和磺胺基因、多重耐药外排基因acrB等8种耐药基因。结果78株沙门菌对12种药物有不同程度耐药(1.28%~74.35%)。得到9株多重耐药菌株,其中5株检出TEM型β内酰胺酶基因;7株耐氯霉素的伤寒沙门菌菌株中,2株仅检出catA基因,1株仅检出catB基因,1株仅检出cmlA氯霉素外排泵蛋白基因,2株同时检出catA基因和cmlA氯霉素外排泵蛋白基因;2株检出aac(6′)Ⅰb基因,1株检出aac3Ⅱ型氨基糖苷类修饰酶基因;4株检出耐消毒剂和磺胺基因qacEΔ1sul1;6株检出多重耐药外排基因acrB。结论大连地区临床分离的伤寒沙门菌存在严峻的耐药现象,多种耐药基因存在于耐药伤寒沙门菌中,可能是导致菌株对多种抗菌药物耐药的原因。 相似文献
17.
目的分析医院耐甲氧西林金黄色葡萄球菌(MRSA)的分布及耐药情况,为临床治疗金黄色葡萄球菌医院感染提供科学依据。方法对618株金黄色葡萄球菌进行常规鉴定,用K—B法对其进行药敏试验。结果5年MRSA的平均检出率为51.9%(321/618),MRSA感染高发主要科室为ICU、神经外科、神经内科,MRSA检出率前三位的科室为神经外科(84.1%)、ICU(76.3%)、呼吸内科(61.3%),标本来源主要为痰液,占67.3%,检出率82.4%。MRSA对万古霉素、替考拉宁、利奈唑胺保持100%敏感,对氯霉素、米诺环素、复方新诺明等的耐药率较低,对其他药物都保持了65%以上的高耐药率。结论对重点科室监控,合理使用抗生素,严格执行无菌操作,采取有效的消毒隔离,尽量减少侵袭性操作等措施是控制并减少MRSA感染的重要环节。 相似文献
18.
Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes 总被引:4,自引:0,他引:4
Marjorie J. Arca John C. Krauss Scott E. Strome Mark J. Cameron A. E. Chang 《Cancer immunology, immunotherapy : CII》1996,42(4):237-245
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete
interleukin-2 (IL-2), IL-4, interferon γ (IFNγ) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters
were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells
derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFNγ and IL-4
partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be
achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the
growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting
tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy.
Neither IL-2 nor IFNγ secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found
to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not
lead to enhanced induction of immune T cells. GM-CSF secretion was found to up-regulate B7-1 expression in TDLN, consistent
with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by
cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability
of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T
cell immune reactivity to the poorly immunogenic BL6 tumor.
Received: 30 January 1996 / Accepted: 22 March 1996 相似文献
19.
Koichiro Abe Mamoru Harada Koji Tamada Osamu Ito Tieli Li Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1997,45(5):225-233
Both natural killer (NK) cells and macrophages are thought to be the main effectors responsible for early antitumor defense.
In this study, we investigated the role of tumor-infiltrating NK cells in initiating nitric oxide (NO) production by tumor-associated
macrophages (TAM). The in vivo depletion of NK cells prior to the i.p. inoculation of melanoma cells resulted in a significant
decrease in the NO production of the TAM prepared from the peritoneal exudate cells (PEC). Such prior NK cell depletion also
decreased the ability of TAM to show any antitumor activity in vitro. The addition of N
G-monomethyl-L-arginine (Me-L-Arg) to the culture partially inhibited the ability of TAM to suppress the proliferation of melanoma cells and also decreased
their cytolytic activity against melanoma cells. These results suggest that the TAM exhibited both cytostatic and cytolytic
activities through their NO production. In an in vivo assay, the administration of Me-L-Arg permitted the more rapid growth of i.p. inoculated melanoma cells compared with the control. On the other hand, the decreased
NO production of TAM, resulting from the prior NK cell depletion, was restored by the i.p. administration of interferon γ
(IFNγ). In addition, the in vivo administration of anti-IFNγ mAb into mice inoculated i.p. with melanoma cells also significantly
decreased the NO production of TAM in peritoneal exudate cells. Furthermore, the tumor-infiltrating NK cells produced a considerable
level of IFNγ. Overall, these results indicate that early-appearing tumor-infiltrating NK cells play an important role in
the NO production of TAM through their IFNγ production.
Received: 11 March 1997 / Accepted: 31 July 1997 相似文献
20.
The risk of acquisition of resistance to chemotherapy remains a major hurdle in the management of various types of cancer patients. Several cellular and noncellular mechanisms are involved in developing both intrinsic and acquired resistance in cancer cells toward chemotherapy. This review covers the various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR mechanisms. Extensive studies have been conducted during the last several decades to enhance the efficacy of chemotherapy by suppressing or evading these MDR mechanisms including the use of new anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanocarriers, and RNA interference (RNAi) therapy. 相似文献