Identification of the minimal glycopeptide core recognized by T cells in a model for rheumatoid arthritis

Holm, Lotta; Kjellén, Peter; Holmdahl, Rikard; Kihlberg, Jan

doi:10.1016/j.bmc.2004.10.011

Cited by 17 publications

(23 citation statements)

References 34 publications

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“…18 This position was therefore kept constant and nonglycosylated in order to simplify the synthesis of the peptide library. However, it should be stressed that GalHyl plays an extremely important role in T-cell responses and thus warrants further study regarding autoimmune response.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

et al. 2007

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Presentation of (glyco)peptides by the class II major histocompatibility complex molecule Aq to T cells plays a central role in collagen-induced arthritis, an animal model for the autoimmune disease rheumatoid arthritis. A peptide library was designed using statistical molecular design in amino acid space in which five positions in the minimal mouse collagen type II binding epitope CII260-267 were varied. A substantially reduced peptide library of 24 peptides with diverse and representative molecular characteristics was selected, synthesized, and evaluated for the binding strength to Aq. A multivariate QSAR model was established by correlating calculated descriptors, compressed to its principle properties, with the binding data using partial least-square regression. The model was successfully validated by an external test set. Interpretation of the model provided a molecular property binding motif for peptides interacting with Aq. The information may be useful in future research directed toward new treatments of rheumatoid arthritis.

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Section: Resultsmentioning

confidence: 99%

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

et al. 2007

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“…61,62 Moreover, other PTMs can also generate immunogenic epitopes, such as phosphorylation 63 and glycosylation. 64 The z scale based method described here, which utilizes variable selection, is an effective and efficient approach to the QSAR modeling of peptide-protein interactions of any type. In the context of peptide-MHC binding, we have demonstrated, and verified experimentally, that this method is as effective as other QSAR techniques based on an indicator variable representation of peptide sequences.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Peptide−Protein Binding Using Amino Acid Descriptors: Prediction and Experimental Verification for Human Histocompatibility Complex HLA-A*0201

et al. 2005

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Amino acid descriptors are often used in quantitative structure-activity relationship (QSAR) analysis of proteins and peptides. In the present study, descriptors were used to characterize peptides binding to the human MHC allele HLA-A*0201. Two sets of amino acid descriptors were chosen: 93 descriptors taken from the amino acid descriptor database AAindex and the z descriptors defined by Wold and Sandberg. Variable selection techniques (SIMCA, genetic algorithm, and GOLPE) were applied to remove redundant descriptors. Our results indicate that QSAR models generated using five z descriptors had the highest predictivity and explained variance (q 2 between 0.6 and 0.7 and r 2 between 0.6 and 0.9). Further to the QSAR analysis, 15 peptides were synthesized and tested using a T2 stabilization assay. All peptides bound to HLA-A*0201 well, and four peptides were identified as high-affinity binders.

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“…Experiments with CII 256-270 have also shown that this peptide sequence can inhibit the progression of CIA [40,44]. It has been suggested that CII 260-267 is the immunodominant core [40,44]. Another major immunodominant epitope (CII 707-721 , CII-1) that we studied has previously been found to elicit a significant proliferative T-cell response [41].…”

Section: Discussionmentioning

confidence: 80%

“…The selection of CII peptides used in this the present study was based on previous studies showing that certain epitopes such as CII 256-270 can bind to I-A q MHC class II molecules [40,43]. Experiments with CII 256-270 have also shown that this peptide sequence can inhibit the progression of CIA [40,44]. It has been suggested that CII 260-267 is the immunodominant core [40,44].…”

Section: Discussionmentioning

confidence: 99%

Bifunctional Peptide Inhibitors Suppress Interleukin-6 Proliferation and Ameliorates Murine Collagen-Induced Arthritis

Kiptoo¹

2014

J Clin Cell Immunol

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The objective of this study is to evaluate the efficacy and potential mechanism of action of type-II collagen bifunctional peptide inhibitor (CII-BPI) molecules in suppressing rheumatoid arthritis in the collagen-induced arthritis (CIA) mouse model. CII-BPI molecules (CII-BPI-1, CII-BPI-2, and CII-BPI-3) were formed through conjugation between an antigenic peptide derived from type-II collagen and a cell adhesion peptide LABL (CD11a237-246) from the I-domain of LFA-1 via a linker molecule. The hypothesis is that the CII-BPI molecules simultaneously bind to MHC-II and ICAM-1 on the surface of APC and block maturation of the immunological synapse. As a result, the differentiation of naïve T cells is altered from inflammatory to regulatory and/or suppressor T cells. The efficacies of CII-BPI molecules were evaluated upon intravenous injections in CIA mice. Results showed that CII-BPI-1 and CIIBPI-2 suppressed the joint inflammations in CIA mice in a dose-dependent manner and were more potent than the respective antigenic peptides alone. CII-BPI-3 was not as efficacious as CII-BPI-1 and CII-BPI-2. Significantly less joint damage was observed in CII-BPI-2 and CII-2 treated mice than in the control. The production of IL-6 was significantly lower at the peak of disease in mice treated with CII-BPI-2 compared to those treated with CII-2 and control. In conclusion, this is the first proof-of-concept study showing that BPI molecules can be used to suppress RA and may be a potential therapeutic strategy for the treatment of rheumatoid arthritis.

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Identification of the minimal glycopeptide core recognized by T cells in a model for rheumatoid arthritis

Cited by 17 publications

References 34 publications

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Analysis of Peptide−Protein Binding Using Amino Acid Descriptors: Prediction and Experimental Verification for Human Histocompatibility Complex HLA-A*0201

Bifunctional Peptide Inhibitors Suppress Interleukin-6 Proliferation and Ameliorates Murine Collagen-Induced Arthritis

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Identification of the minimal glycopeptide core recognized by T cells in a model for rheumatoid arthritis

Cited by 17 publications

References 34 publications

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule AqAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule AqAssociated with Autoimmune Arthritis

Analysis of Peptide−Protein Binding Using Amino Acid Descriptors: Prediction and Experimental Verification for Human Histocompatibility Complex HLA-A*0201

Bifunctional Peptide Inhibitors Suppress Interleukin-6 Proliferation and Ameliorates Murine Collagen-Induced Arthritis

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Product

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Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis

Quantitative Structure−Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule A^qAssociated with Autoimmune Arthritis