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Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1

Identifieur interne : 000400 ( Istex/Corpus ); précédent : 000399; suivant : 000401

Definition of MHC-restricted CTL epitopes from non-variable number of tandem repeat sequence of MUC1

Auteurs : Geoffrey A. Pietersz ; Wenjun Li ; Carla Osinski ; Vasso Apostolopoulos ; Ian F. C Mckenzie

Source :

RBID : ISTEX:1E27E87D868943AC8CC7C000728469978D5F3BC6

English descriptors

Abstract

Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.

Url:
DOI: 10.1016/S0264-410X(99)00515-0

Links to Exploration step

ISTEX:1E27E87D868943AC8CC7C000728469978D5F3BC6

Le document en format XML

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<div type="abstract" xml:lang="en">Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</div>
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<note type="content">Fig. 1: Assay for HMFG and mannan. (a) Inhibition of binding of anti-MUC1 antibody to HMFG by competitor preparations of HMFG (○) and mannan–HMFG (⋅). (b) Binding of mannan–HMFG (⋅) and HMFG (○) to anti-MUC1 antibody and Con A detected by a radioimmunoassay.</note>
<note type="content">Fig. 2: A2 KbMUC1 double transgenic mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Cytotoxic activity of the effector cells were measured on 51Cr-labelled MCF7 with (■) or without cold K562 (⋅); BT20 (□) or ME272 (○).</note>
<note type="content">Fig. 3: C57BL/6 and BALB/c mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Lysis of P815 (a) or RMA (c) cells pulsed with various 9-mer peptides from the intracellular peptide 471–493; Lysis of P815 (b) or RMA (d) cells pulsed with various 9-mer peptides from the extracellular peptides 33–103 and 51–70 and (e) Lysis of P815 cells pulsed with YYQELQRDI and RMA-MUC1 cells pulsed with SAPDNRPAL. As controls for peptide pulsing and antigen-specific cell lysis, known peptide antigens were used and are shown in each panel and described in the text.</note>
<note type="content">Table 1: Diagramatic structure of MUC1 and sequences of the synthetic peptidesa</note>
<note type="content">Table 2: CTLp frequencies in spleens of mice immunised with mannan–HMFG</note>
<note type="content">Table 3: Mice immunised with mannan–HMFG: CTLp frequencies to various non-VNTR peptides and their predicted CTL epitopes</note>
<note type="content">Table 4: Experimentally determined and predicted mouse and human CTL epitopes in the MUC1 VNTR</note>
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<ce:simple-para>Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/K
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<abstract lang="en">Abstract: Mucin1 (MUC1) is expressed ubiquitously on breast cancer cells and is a potential target for the generation of cytotoxic T cells for vaccination against breast cancer. Thus far studies of the immunogenicity of MUC1 have used peptides from the variable number of tandem repeat (VNTR); mice so immunised can generate strong cellular and antibody responses to the VNTR of human MUC1. We now demonstrate that significant CTL and CTLp can be induced to other regions of MUC1. Using the whole native MUC1 molecule, the human milk fat globule membrane antigen (HMFG) linked to mannan, cytotoxic T cell precursors (CTLp) can be generated in BALB/c, C57BL/6, transgenic HLA-A*0201/Kb and double transgenic HLA-A*0201/Kb×human MUC1 (A2 KbMUC1) mice. By immunising with HMFG and testing selectively on (a) extracellular (non-VNTR); (b) VNTR and (c) intracellular peptides, it was shown that all three regions generated effective CTL. Further, the CTL responses to non-VNTR peptides were as strong as those generated to the VNTR. Epitope prediction algorithms were not particularly helpful to describe CTL epitopes: overlapping peptides had to be synthesised and tested to find the epitopes. Thus, for CTL generation, the whole HMFG molecule is a powerful immunogen when linked to mannan, especially as multiple peptide epitopes for presentation by many Class I molecules are contained within the one molecule. Furthermore, Class I restricted MUC1 CTL were generated in double transgenic A2 KbMUC1 mice by immunising with mannan-native mucin (HMFG), suggesting that tolerance to MUC1 can be overcome with mannan–HMFG.</abstract>
<note type="content">Fig. 1: Assay for HMFG and mannan. (a) Inhibition of binding of anti-MUC1 antibody to HMFG by competitor preparations of HMFG (○) and mannan–HMFG (⋅). (b) Binding of mannan–HMFG (⋅) and HMFG (○) to anti-MUC1 antibody and Con A detected by a radioimmunoassay.</note>
<note type="content">Fig. 2: A2 KbMUC1 double transgenic mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Cytotoxic activity of the effector cells were measured on 51Cr-labelled MCF7 with (■) or without cold K562 (⋅); BT20 (□) or ME272 (○).</note>
<note type="content">Fig. 3: C57BL/6 and BALB/c mice were immunised with mannan–HMFG and splenocytes were used in CTL assays. Lysis of P815 (a) or RMA (c) cells pulsed with various 9-mer peptides from the intracellular peptide 471–493; Lysis of P815 (b) or RMA (d) cells pulsed with various 9-mer peptides from the extracellular peptides 33–103 and 51–70 and (e) Lysis of P815 cells pulsed with YYQELQRDI and RMA-MUC1 cells pulsed with SAPDNRPAL. As controls for peptide pulsing and antigen-specific cell lysis, known peptide antigens were used and are shown in each panel and described in the text.</note>
<note type="content">Table 1: Diagramatic structure of MUC1 and sequences of the synthetic peptidesa</note>
<note type="content">Table 2: CTLp frequencies in spleens of mice immunised with mannan–HMFG</note>
<note type="content">Table 3: Mice immunised with mannan–HMFG: CTLp frequencies to various non-VNTR peptides and their predicted CTL epitopes</note>
<note type="content">Table 4: Experimentally determined and predicted mouse and human CTL epitopes in the MUC1 VNTR</note>
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