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1.
Antibodies reactive with the protein core of MUC1 mucin are present in ovarian cancer patients and healthy women 总被引:6,自引:0,他引:6
Elizabeth R. Richards Peter L. Devine Rachel J. Quin J. Darrell Fontenot Bruce G. Ward M. A. McGuckin 《Cancer immunology, immunotherapy : CII》1998,46(5):245-252
Antibodies reactive with peptide epitopes on the core protein of MUC1 epithelial mucin have been demonstrated in some patients
with adenocarcinomas. Because these epitopes can be exposed on MUC1 in the serum of healthy women, we measured concentrations
of MUC1-reactive antibodies in the serum of healthy pregnant and non-pregnant women, and in patients with benign and malignant
ovarian tumours. Antibodies were measured in an enzyme-linked immunosorbent assay utilising a synthetic peptide corresponding
to a 105-amino-acid segment of the MUC1 tandem repeat region (5.25 repeats). MUC1-reactive antibodies were always of an IgM
isotype and concentrations were highest in young healthy women and declined progressively with age (P = 0.0006) concomitantly with increasing serum MUC1 levels (P = 0.003). Regardless of age, antibody levels were lower in cancer patients than in healthy women (P<0.0001), but MUC1 levels were much higher in cancer patients (P<0.0001). Although high antibody levels were associated with greater survival in ovarian cancer (P = 0.015), multivariate regression analysis showed that this was not a significant independent prognostic indicator after
consideration of the International Federation of Gynaecology and Obstetrics (FIGO) stage, histological type, serum MUC1 levels
and age. Serial measurement of MUC1 and MUC1 antibodies during treatment in 18 patients with ovarian cancer and throughout
pregnancy in 10 women showed a negative correlation between alterations in MUC1 and MUC1 antibodies. These results show that
MUC1-peptide-reactive antibodies are present in the serum of healthy women and women with cancer and that they probably form
immune complexes with MUC1, but provide no evidence for an augmentation of the humoral immune response to MUC1 in ovarian
cancer
Received: 8 January 1998 / Accepted: 26 February 1998 相似文献
2.
MUC1-specific immune responses in human MUC1 transgenic mice immunized with various human MUC1 vaccines 总被引:12,自引:0,他引:12
Acres B Apostolopoulos V Balloul JM Wreschner D Xing PX Ali-Hadji D Bizouarne N Kieny MP McKenzie IF 《Cancer immunology, immunotherapy : CII》2000,48(10):588-594
Analyses of MUC1-specific cytotoxic T cell precursor (CTLp) frequencies were performed in mice immunized with three different
MUC1 vaccine immunotherapeutic agents. Mice were immunized with either a fusion protein comprising MUC1 and glutathione S-transferase (MUC1-GST), MUC1-GST fusion protein coupled to mannan (MFP) or with a recombinant vaccinia virus expressing both
MUC1 and interleukin-2. Mouse strain variations in immune responsiveness have been observed with these vaccines. We have constructed
mice transgenic for the human MUC1 gene to study MUC1-specific immune responses and the risk of auto-immunity following MUC1 immunization. Transgenic mice immunized
with MUC1 were observed to be partially tolerant in that the MUC1-specific antibody response is lower than that observed in
syngeneic but non-transgenic mice. However, a significant MUC1-specific CTLp response to all three vaccines was observed,
indicating the ability to overcome T cell, but to a lesser extent B cell, tolerance to MUC1 in these mice. Histological analysis
indicates no evidence of auto-immunity to the cells expressing the human MUC1 molecule. These results suggest that it is possible
to generate an immune response to a cancer-related antigen without damage to normal tissues expressing the antigen.
Received: 7 July 1999 / Accepted: 26 August 1999 相似文献
3.
Denton G Brady K Lo BK Murray A Graves CR Hughes OD Tendler SJ Laughton CA Price MR 《Cancer immunology, immunotherapy : CII》1999,48(1):29-38
A recombinant diabody fragment based on the anti-MUC1 monoclonal antibody, C595 has been produced in a bacterial expression
system. Substitution of a 7-amino-acid linker sequence (Gly6Ser) for the original single-chain (sc)Fv 15-amino-acid linker (Gly4Ser)3, using polymerase-chain-reaction-based strategies, forces variable heavy (VH) and light (VL) domains to pair with complementary domains on neighbouring scFv molecules, forming a scFv dimer (diabody). This recombinant
protein shows similar binding characteristics to the parental C595 monoclonal antibody. The ability to bind to MUC1 mucin
on carcinoma cell surfaces will allow its potential as a diagnostic and therapeutic reagent of clinical utility to be investigated.
Received: 16 September 1998 / Accepted: 2 December 1998 相似文献
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5.
Zimmermann GL Krantz MJ Kane KP Longenecker BM 《Cancer immunology, immunotherapy : CII》2000,49(6):305-313
We report here the development of a mouse mammary adenocarcinoma cell line containing full-length human MUC1 cDNA that can
be more lethal than the parental cell line. The metastatic murine mammary adenocarcinoma cell line 410.4 was transfected with
cDNA coding for a 42-tandem-repeat version of human MUC1. Two cell lines were selected, one for stable, high expression in
vitro of cell-surface MUC1 (GZHi) and one for stable, low expression in vitro of cell-surface MUC1 (GZLo). Following subcutaneous
challenge of CB6F1 mice with various doses of tumor cells, GZHi tumors showed loss of MUC1 expression; negligible amounts
of serum MUC1 mucin were detected and the mice survived longer than mice challenged with GZLo or wild-type (410.4) tumor cells.
Mice challenged with GZLo tumor cells had shorter survival times than mice challenged with either GZHi or 410.4 tumor cells.
GZLo-challenged mice that showed rapidly increasing serum MUC1 mucin levels several weeks prior to death had a shorter survival
than mice without detectable rising MUC1 serum levels. Surprisingly, SCID-BEIGE mice challenged with GZLo cells also survived
for a shorter time than those challenged with either GZHi or 410.4 cells. This suggests that MUC1 mucin may also enhance the
aggressiveness of GZLo tumors by non-immune mechanisms.
Received: 30 November 1999 / Accepted: 13 March 2000 相似文献
6.
Parry S Hanisch FG Leir SH Sutton-Smith M Morris HR Dell A Harris A 《Glycobiology》2006,16(7):623-634
The MUC1 mucin is an important tumor-associated antigen that shows extensive glycosylation in vivo. The O-glycosylation of this molecule, which has been well characterized in many cell types and tissues, is important in conferring the unusual biochemical and biophysical properties on a mucin. N-Glycosylation is crucial to the folding, sorting, membrane trafficking, and secretion of many proteins. Here, we evaluated the N-glycosylation of MUC1 derived from two sources: endogenous MUC1 isolated from human milk and a recombinant epitope-tagged MUC1F overexpressed in Caco2 colon carcinoma cells. N-Glycans on purified MUC1F/MUC1 were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), gas chromatography-mass spectrometry (GC-MS), and CAD-ESI-MS/MS. The spectra indicate that MUC1F N-glycans have compositions consistent with high-mannose structures (Hex(5-9)HexNAc(2)) and complex/hybrid-type glycans (NeuAc(0-3)Fuc(0-3)Hex(3-8)HexNAc(3-7)). Many of the N-glycan structures are identical on MUC1F and native MUC1; however, a marked difference is seen between the N-glycans on membrane-bound and secreted forms of the native molecule. 相似文献
7.
F Carvalho R Seruca L David A Amorim M Seixas E Bennett H Clausen M Sobrinho-Simoes 《Glycoconjugate journal》1997,14(1):107-111
Gastric carcinoma is a major cause of cancer death worldwide and, like most human cancers, probably develops after environmental insults acting on normal individuals and/or individuals with increased genetic susceptibility. Mucins are attractive molecules to study the relationship between genetics and environment because they play an important role in the protection of gastric mucosa against environmental insults and exhibit a highly polymorphic genetic variation. We performed a case-control study using Southern blot analysis to evaluate the MUC1 gene polymorphism in a series of blood donors (n=324) and in patients with gastric carcinoma (n=159). We found that the distribution of MUC1 alleles is significantly different in the two populations and that small MUC1 alleles and small MUC1 genotypes are significantly more frequent in patients with gastric carcinoma than in controls. Individuals with small MUC1 genotypes are at increased risk for gastric carcinoma development. 相似文献
8.
经高速离心从正常人乳中获得人乳汁颗粒膜(HMFGM),产量约0.4g/L。经进一步破碎、脱脂及sepharose CL-4B柱纯化,获得含MUC1粘蛋白的组分,并经SDS—PAGE、Western—blot及ELISA鉴定后,免疫家兔制备多抗。结果表明,进一步凝胶过滤获得MUC1粘蛋白,行SDS—PAGE后经希夫试剂和考马斯亮蓝染色呈单一条带,表观相对分子质量大干205000。Western—blot及ELISA结果表明可与MUC1特异性抗体结合。制备获得的多抗经ELISA测定效价为1:64000~1:128000。表明建立了MUC1粘蛋白的纯化方法,获得的MUC1粘蛋白及其抗体可进一步用于MUC1检测及其功能的研究。 相似文献
9.
Xiaohong Liu Jan Sejbal George Kotovych R. Rao Koganty Mark A. Reddish Linda Jackson Sham S. Gandhi Aubrey J. Mendonca B. Michael Longenecker 《Glycoconjugate journal》1995,12(5):607-617
Translation of an immune response into therapy is probably the toughest task in designing vaccines for cancer due to the heterogeneity of the cell surface antigens which display tremendous variations in glycoforms. Consequently, a small segment (antigen) of the cancer-associated mucin, in spite of generating antigen-specific immune responses, may be limited in therapeutic value. It is important that the synthetic segment resembles the native cancer-associated mucin in both structure and conformation. Synthetic cancer associated mucin derived 16 amino acid peptide GVTSAPDTRAPAPGSTA and its partially glycosylated forms have demonstrated specific binding to two monoclonal antibodies, B27.29 and BCP8, raised against the native cancer associated mucin, MUC-1 and a MUC-1 derived synthetic peptide, respectively. In spite of the structural similarities at the core peptide level of both glycosylated and unglycosylated peptides, it appears that partial glycosylation does not inhibit and even slightly enhances binding to the MAb B27.29 indicating that the glycosylated synthetic peptide more closely resembles the native mucin epitope recognized by MAb B27.29. From molecular dynamic simulations using NMR derived distance constraints, both glycosylated and unglycosylated peptides have shown a type I turn involving the same amino acids in both glycosylated and unglycosylated peptides. The GalNAc attached to the threonine (T3) and serine (S4) in the 16 amino acid sequence has not imposed any conformational changes to the peptide backbone nor has offered severe steric resistance to the binding of either antibody to the glycopeptides as indicated by hapten inhibition studies. Nevertheless, all peptides have displayed glycosylation dependent specificities in binding to these antibodies, i.e. the glycosylated peptides demonstrated relative higher affinities to the native mucin antibody B27.29 while the unglycosylated peptide is more specific to the MAb BCP8. Immune responses generated by these synthetic glycopeptides are highly specific in recognizing the native cancer associated mucin. 相似文献
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Hattrup CL Fernandez-Rodriguez J Schroeder JA Hansson GC Gendler SJ 《Biochemical and biophysical research communications》2004,316(2):364-369
The MUC1 tumor antigen is overexpressed on most breast tumors and metastases. It interacts with signaling proteins such as the ErbB kinases and beta-catenin, and is involved in mammary gland oncogenesis and tumor progression. Herein, we report a novel interaction between MUC1 and adenomatous polyposis coli (APC), a tumor suppressor involved in downregulating beta-catenin signaling. Initially identified in colorectal cancer, APC is also downregulated in breast tumors and presumably involved in mammary carcinogenesis. MUC1 and APC co-immunoprecipitate from the ZR-75-1 human breast carcinoma cell line and co-localize in mouse mammary glands and tumors. These studies also indicate that the association of MUC1 and APC may be increased by epidermal growth factor stimulation. Intriguingly, the co-immunoprecipitation of MUC1 and APC increases in human breast tumors and metastases as compared to adjacent normal tissues, indicating that this association may play a role in the formation and progression of breast tumors. 相似文献
13.
von Mensdorff-Pouilly S Kinarsky L Engelmann K Baldus SE Verheijen RH Hollingsworth MA Pisarev V Sherman S Hanisch FG 《Glycobiology》2005,15(8):735-746
The human epithelial cancer mucin MUC1 is able to break tolerance and to induce humoral immune responses in healthy subjects and in cancer patients. We recently showed that clusters of sequence-variant repeats are interspersed in the repeat domain of MUC1 at high frequency, which should contribute to the structural and immunological features of the mucin. Here we elucidated the potential effects exerted by sequence-variant repeats on their O-glycosylation. Evidence from in vitro glycosylation with polypeptide N-acetylgalactosaminyltransferases GalNAc-T1 and GalNAc-T2 in concert with mass spectrometric analyses of in vivo glycosylated MUC1 probes from transiently transfected HEK293 cells indicated reduced glycosylation densities of repeats with three concerted replacements: AHGVTSAPESRPAPGSTAPA. The Pro to Ala replacement in STAPA exerts not only proximal effects on the ppGalNAc-T2 preferred site at -3 and -4, but also more distant effects on the ppGalNAc-T1 preferred site at -15 (TSAPESRPAPGSTAPA). We also examined the conformational changes of MUC1 glycopeptides induced by the concerted DT to ES replacements and revealed a higher conformational flexibility of ES/P peptides compared to DT/P peptides. Differences in conformational flexibilities and in O-glycosylation densities could underlie the observed differential humoral responses in humans. We were able to show that the natural immunoglobulin G (IgG) responses to the repeat domain of MUC1 in sera from nonmalignant control subjects are preferentially directed to variant repeat clusters. In contrast, the IgG response in patients with adenocarcinoma shifted to higher frequencies of preferential DTR peptide binding. 相似文献
14.
目的:检测胃癌组织中VEGF和MUC1的表达情况,研究二者与胃癌生物学行为之间的关系。方法:应用免疫组织化学SP法检测VEGF和MUC1在胃癌组织和癌旁组织中的表达情况。结果:胃癌组织中VEGF的阳性表达明显高于癌旁组织,两者之间差异存在统计学意义(P0.05),VEGF在胃癌组织中的表达与胃癌浸润深度、有无远处转移、有无淋巴结转移、TNM分期有关,之间差异存在统计学意义(P0.05);胃癌组织中MUC1的阳性表达明显高于癌旁组织,两者之间差异存在统计学意义(P0.05),MUC1在胃癌组织中的表达与分化程度、TNM分期、淋巴结转移、远处转移有关,差异有统计学意义(P0.05);胃癌患者组织VEGF与MUC1的表达水平呈正相关(r=0.210,P0.05)。结论:VEGF和MUC1在胃癌发生、发展和转移过程中起重要作用,可能成为检测胃癌的重要肿瘤标志物。 相似文献
15.
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
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Mehdy Elahi S Bergeron J Nagy E Talbot BG Harpin S Shen SH Elazhary Y 《FEMS microbiology letters》1999,171(2):107-114
A recombinant fowlpox virus (rFPV/E2) expressing the E2 protein of bovine viral diarrhea virus (BVDV) was constructed and characterized. Mice were immunized with recombinant virus and both humoral and cellular immune responses were studied. rFPV/E2 induced BVDV-specific antibodies which were detected by ELISA. In addition, mouse sera were shown to neutralize BVDV. A cytokine ELISA assay revealed that mice vaccinated with rFPV/E2 induced 7-fold more interferon-gamma than parental fowlpox virus. 相似文献
18.
Sørensen AL Reis CA Tarp MA Mandel U Ramachandran K Sankaranarayanan V Schwientek T Graham R Taylor-Papadimitriou J Hollingsworth MA Burchell J Clausen H 《Glycobiology》2006,16(2):96-107
The MUC1 mucin represents a prime target antigen for cancer immunotherapy because it is abundantly expressed and aberrantly glycosylated in carcinomas. Attempts to generate strong humoral immunity to MUC1 by immunization with peptides have generally failed partly because of tolerance. In this study, we have developed chemoenzymatic synthesis of extended MUC1 TR glycopeptides with cancer-associated O-glycosylation using a panel of recombinant human glycosyltransferases. MUC1 glycopeptides with different densities of Tn and STn glycoforms conjugated to KLH were used as immunogens to evaluate an optimal vaccine design. Glycopeptides with complete O-glycan occupancy (five sites per repeat) elicited the strongest antibody response reacting with MUC1 expressed in breast cancer cell lines in both Balb/c and MUC1.Tg mice. The elicited humoral immune response showed remarkable specificity for cancer cells suggesting that the glycopeptide design holds promise as a cancer vaccine. The elicited immune responses were directed to combined glycopeptide epitopes, and both peptide sequence and carbohydrate structures were important for the antigen. A MAb (5E5) with similar specificity as the elicited immune response was generated and shown to have the same remarkable cancer specificity. This antibody may hold promise in diagnostic and immunopreventive measures. 相似文献
19.
目的:探讨新型呼肠病毒R4株S片段免疫小鼠后引发的免疫应答。方法构建4个不同S基因节段的重组真核表达质粒,并免疫小鼠;ELISA检测血清以研究R4特异性抗体升高水平,并对其抗体亚型进行鉴定;ELISPOT检测小鼠淋巴细胞INF-γ的表达情况。结果与对照组相比,4个重组质粒免疫的小鼠血清都有明显的R4特异性抗体升高,尤其以S1和S3基因免疫后抗体水平较高,且均以IgG2a占绝对优势;S1基因免疫组小鼠的细胞免疫应答最强。结论 S1基因重组质粒免疫小鼠后可同时引发较强的体液免疫和细胞免疫应答,是较为理想的疫苗备选基因片段。 相似文献