A Conformationally-Constrained MHC Class II I-Ag7-Derived Peptide Protects NOD Mice from the Development of Diabetes

Dunsavage, Melina B; O’Leary, Cornelius J; Baumgart, Trageen; Solvason, Nanette; Howard, Maureen; Lafferty, Kevin J.; Deshpande, Shrikant; Reich, E.

doi:10.1006/jaut.1999.0277

Cited by 15 publications

(17 citation statements)

References 35 publications

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“…However, modifications between P2-P3, P3-P4, P5-P6 and P8-P9 dramatically reduced peptide binding to HLA-A2 [103]. Finally, oral administration of the retro-inverso analogue of MBP [87][88][89][90][91][92][93][94][95][96][97][98][99] was shown to decrease experimental autoimmune encephalitis in mice while being resistant to proteolytic degradation, highlighting the therapeutic value of retro-inverso peptides [104].…”

Section: Multiple Epitope Trojan Antigen Peptide Vaccinesmentioning

confidence: 99%

“…The design of conformationally constrained peptides which can bind to MHC and interact with TcR to elicit a strong immune response is challenging and may explain why no cyclic peptides have been designed to date for cancer immunotherapeutic applications. Cyclic peptides have, however, been developed for vaccination protocols in diseases such as multiple sclerosis (MS) [85][86][87][88][89][90] and diabetes [91,92] although the mechanism of inhibition remains to be elucidated.…”

Section: Peptide Cyclizationmentioning

confidence: 99%

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Insights into Peptide-Based Vaccine Design for Cancer Immunotherapy

Lazoura

Apostolopoulos²

2005

CMC

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The presentation of peptides derived from tumor associated proteins (TAAs) by the major histocompatibility complex (MHC) to T cell receptor (TcR) initiates a cascade of events that constitute the immune response. Eliciting an effective immune response, however, requires the coordinated regulation of both the cellular and humoral arms of the immune system. The design of effective peptide-based vaccines for cancer immunotherapeutic applications, therefore, requires intimate knowledge and understanding of peptide-MHC (pMHC) as well as TcR-pMHC interactions. Despite the wealth of information available to date from X-ray crystallographic and biological studies, the task of rationally designing peptide-based vaccines that can effectively prevent and/or treat cancer cell proliferation remains challenging. The complexity of interactions involved are not readily predictable and are further complicated by the involvement of surrounding molecules in vivo, which can lead to reduced biological activity and/or unwanted side effects. Furthermore, the delivery of peptide-based vaccines into the cell, for further processing and presentation to effector cell, represents an additional challenge which needs to be addressed. The incorporation of appropriate chemical entities into peptide-based vaccines can improve cellular uptake thereby enhancing biological activity. Finally, the susceptibility of peptide-based vaccines to enzymatic degradation warrants the need for the incorporation of non-natural amino acids, retro-inversion and/or cyclization to improve bioavailability essentially reducing the required dosage with minimum side effects.

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Section: Multiple Epitope Trojan Antigen Peptide Vaccinesmentioning

confidence: 99%

Section: Peptide Cyclizationmentioning

confidence: 99%

Insights into Peptide-Based Vaccine Design for Cancer Immunotherapy

Lazoura

Apostolopoulos²

2005

CMC

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“…Partially retro-inverso analogue of the antigenic peptide M 58-66 derived from the influenza matrix protein, modified between P1-P2, showed increased stability and high HLA-A2 binding ability [109]. In contrast to MHC class I peptide binding, loss of both the ability to bind to MHC class II molecules and to elicit specific T cells was observed for retro-inverse analogues of toxin [24][25][26][27][28][29][30][31][32][33][34][35][36] , HEL [103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] , rep [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] and OVA 323-339 [110].…”

Section: Retro-inverso Peptidesmentioning

confidence: 99%

“…Despite the enormous potential, no cyclic peptides have been designed for immunotherapeutic applications in cancer, which may be attributed to the difficult design process of constrained epitopes which can bind both to MHC and, in turn, bind to TcR to elicit a strong immune response. Cyclic peptides have, however, been developed for vaccination protocols in diseases such as multiple sclerosis and diabetes [98][99][100][101][102][103][104][105].…”

Section: Main-chain and Side-chain Cyclic Peptidesmentioning

confidence: 99%

Rational Peptide-Based Vaccine Design for Cancer Immunotherapeutic Applications

Lazoura

Apostolopoulos²

2005

CMC

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Immune responses to cancer cells can be elicited in vivo by administering synthetic peptides derived from proteins uniquely or overexpressed on tumor cells (tumor associated antigens--TAAs). Peptides derived from TAAs are presented in the context of major histocompatibility complex (MHC) molecules to cytotoxic T cells (CTL), which can recognize and lyze tumor cells. In contrast to peptides derived from an exogenous source (viral or bacterial), tumor peptides bind weakly to MHC class I molecules. The low binding affinity of these peptides makes them poor candidates for vaccination due to the poor immunogenic response produced. In order to enhance antigen recognition and hence immunogenicity, peptide binding affinity for MHC can be initially improved by modifying the "anchor" residues. However, the task at hand is highly unpredictable and minor changes in peptide sequence can alter/abolish the T cell response. Furthermore, despite the wealth of information obtained over the last decade from high resolution X-ray structures of MHC class I in complex with peptides (pMHC) as well as pMHC in complex with T cell receptor (TcR), prediction remains difficult. Nonetheless, peptides represent convenient chemical entities that can be rapidly synthesized in clinical grade for therapeutic applications. Herein, the rationale behind modifying TAAs will be discussed including the synthesis/use of proteolytically tolerant peptides (and peptide mimetics) which incorporate non-natural amino acids, retro-inversion and cyclization to improve bioavailability.

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“…One general approach has been to use peptides to compete for the presentation of the autoimmunity-inducing peptide (19) or to exploit oligomerized peptides with a similar goal (20). Preparations of MHC molecules complexed to a broad repertoire of peptides or prepared with a limited, disease-directed set of peptides are also being evaluated (21,22). Each of these approaches to immune modulation has its own particular advantages and drawbacks.…”

mentioning

confidence: 99%

Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

Chung

Belyakov

Derby

et al. 2001

The Journal of Immunology

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We have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex consisting of H-2Dd and a decamer peptide corresponding to residues 311–320 of the HIV IIIB envelope glycoprotein gp160. When administered at the time of primary immunization with a vaccinia virus vector encoding gp160, the mAb blocks the subsequent appearance of CD8+ CTL with specificity for the immunodominant Ag, P18-I10, presented by H-2Dd. This inhibition is specific for this particular peptide Ag; another H-2Dd-restricted gp160 encoded epitope from a different HIV strain is not affected, and an H-2Ld-restricted epitope encoded by the viral vector is also not affected. Using functional assays and specific immunofluorescent staining with multivalent, labeled H-2Dd/P18-I10 complexes (tetramers), we have enumerated the effects of blocking of priming on the subsequent appearance, avidity, and TCR Vβ usage of Ag-specific CTL. Ab blocking skews the proportion of high avidity cells emerging from immunization. Surprisingly, Vβ7-bearing Ag-specific TCR are predominantly inhibited, while TCR of several other families studied are not affected. The ability of a specific MHC/peptide mAb to inhibit and divert the CD8+ T cell response holds implications for vaccine design and approaches to modulate the immune response in autoimmunity.

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A Conformationally-Constrained MHC Class II I-Ag7-Derived Peptide Protects NOD Mice from the Development of Diabetes

Cited by 15 publications

References 35 publications

Insights into Peptide-Based Vaccine Design for Cancer Immunotherapy

Insights into Peptide-Based Vaccine Design for Cancer Immunotherapy

Rational Peptide-Based Vaccine Design for Cancer Immunotherapeutic Applications

Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

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