Open AccessJournal Article
Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model
Richard M. Tempero,Keita Morikane,Michelle L. VanLith,Sandra J. Gendler,Michael A. Hollingsworth +4 more
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TLDR
Data suggest that endogenous expression of MUC1 protein by M UC1 transgenic mice induces T-cell tolerance to stimulation by MUC2, and will facilitate the investigation of anti-MUC1 immunotherapy formulations.Abstract:
The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57Bl/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.read more
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Recombinant plant-expressed tumour-associated MUC1 peptide is immunogenic and capable of breaking tolerance in MUC1.Tg mice
Julia Pinkhasov,M. Lucrecia Alvarez,Maria Manuela Rigano,Khanrat Piensook,Dalia Larios,Martin Pabst,Josephine Grass,Pinku Mukherjee,Sandra J. Gendler,Amanda Maree Walmsley,Hugh S. Mason +10 more
TL;DR: The results indicate that a plant-derived human tumour-associated antigen is equivalent to the human antigen in the context of immune recognition.
Journal ArticleDOI
MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice
Vani Lakshminarayanan,Nitin T. Supekar,Jie Wei,Dustin B. McCurry,Amylou C. Dueck,Heidi E. Kosiorek,Priyanka Trivedi,Judy M. Bradley,Cathy S. Madsen,Latha B. Pathangey,Dominique B. Hoelzinger,Margreet A. Wolfert,Geert-Jan Boons,Peter A. Cohen,Sandra J. Gendler +14 more
TL;DR: Surprisingly, direct admixture of M UC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC 1 immunoediting, whereas ex vivo activation of the hyperimmune T -cells prior to tumor admixture rendered them curative.
Review Advances of MUC1 as a target for breast cancer immunotherapy
E. Yang,P. X. Xing +1 more
TL;DR: In this article, the authors focus on the recent advance of MUC1 breast cancer immunotherapy currently being investigated and present a review of the recent advances in breast cancer Immunotherapy.
Journal ArticleDOI
Evaluation of nose‐only aerosol inhalation chamber and comparison of experimental results with mathematical simulation of aerosol deposition in mouse lungs
TL;DR: The results suggest that the nose-only inhalation chamber would benefit from significant changes to increase the efficiency of deposition in mice such that it can be used for nebulization of expensive therapeutic drugs.
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Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1.
TL;DR: It is demonstrated that significant CTL and CTLp can be induced to other regions of MUC1 by immunising with mannan-native mucin (HMFG) and testing selectively on extracellular (non-VNTR); and all three regions generated effective CTL.
References
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Journal ArticleDOI
Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes
David Nemazee,Kurt Bürki +1 more
TL;DR: B-cell tolerance in transgenic mice using genes for IgM anti-H–2k MHC class I antibody is studied and it is suggested that very large numbers of autospecific B cells can be controlled by clonal deletion.
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Molecular cloning and expression of human Tumor-associated Polymorphic Epithelial Mucin
Sandra Gendler,Carole A. Lancaster,Joyce Taylor-Papadimitriou,Trevor Duhig,Nigel Peat,Joy Burchell,Lucy Pemberton,El-Nasir Lalani,David Wilson +8 more
TL;DR: The full sequence for PEM, as deduced from cDNA sequences, is reported, with length variations in the tandem repeat result in PEM being an expressed variable number tandem repeat locus.
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Epithelial Mucin Genes
TL;DR: Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed to help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.
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A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats.
TL;DR: It is shown here that all three antibodies react with a synthetic peptide with an amino acid sequence corresponding to that predicted by the tandem repeat, allowing a directed approach to the development of tumor-specific antibodies using synthetic peptides as immunogens.
Journal ArticleDOI
MUC1, the renaissance molecule.
TL;DR: Recent discoveries that suggest that MUC1 may be a multifunctional protein, located on the surfaces of cells as a sensor of the environment, poised to signal to the interior when things go awry are highlighted.