Immunosuppression by Co‐stimulatory Molecules: Inhibition of <scp>CD</scp>2‐<scp>CD</scp>48/<scp>CD</scp>58 Interaction by Peptides from <scp>CD</scp>2 to Suppress Progression of Collagen‐induced Arthritis in Mice

Gokhale, Ameya; Kanthala, Shanthi; Latendresse, John R.; Taneja, Veena; Satyanarayanajois, Seetharama D.

doi:10.1111/cbdd.12138

Cited by 25 publications

(26 citation statements)

References 58 publications

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“…Samples were analyzed as described previously. 12 Using the sample procedure, samples were prepared for HPLC analysis. Another cyclic control peptide (compound 35) was used as an internal standard to get the relative intensity in mass spectra.…”

Section: Methodsmentioning

confidence: 99%

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

et al. 2016

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The interaction between the cell–cell adhesion proteins CD2 and CD58 plays a crucial role in lymphocyte recruitment to inflammatory sites, and inhibitors of this interaction have potential as immunomodulatory drugs in autoimmune diseases. Peptides from the CD2 adhesion domain were designed to inhibit CD2:CD58 interactions. To improve the stability of the peptides, β-sheet epitopes from the CD2 region implicated in CD58 recognition were grafted into the cyclic peptide frameworks of sunflower trypsin inhibitor and rhesus theta defensin. The designed multicyclic peptides were evaluated for their ability to modulate cell–cell interactions in three different cell adhesion assays, with one candidate, SFTI-a, showing potent activity in the nanomolar range (IC50: 51 nM). This peptide also suppresses the immune responses in T cells obtained from mice that exhibit the autoimmune disease rheumatoid arthritis. SFTI-a was resistant to thermal denaturation, as judged by circular dichroism spectroscopy and mass spectrometry, and had a half-life of ~24 h in human serum. Binding of this peptide to CD58 was predicted by molecular docking studies and experimentally confirmed by surface plasmon resonance experiments. Our results suggest that cyclic peptides from natural sources are promising scaffolds for modulating protein–protein interactions that are typically difficult to target with small-molecule compounds.

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Section: Methodsmentioning

confidence: 99%

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

et al. 2016

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“…These compounds contain a peptide from the CD2 protein along with stabilizing moieties, and can interact with both human CD58 and mouse CD48 [112]. The compounds limit staining of CD58+ cells with an anti-CD58 mAb, indicating the specificity of the compound; however, the authors did not report specifically on whether the compounds blocked interactions between CD58 and CD2.…”

Section: Immunoregulatory Roles For Cd48 Determined By Studies In mentioning

confidence: 99%

“…The compounds limit staining of CD58+ cells with an anti-CD58 mAb, indicating the specificity of the compound; however, the authors did not report specifically on whether the compounds blocked interactions between CD58 and CD2. Administration of these CD2 peptides during collagen-induced arthritis in the DBA mouse attenuated both clinical and histological signs of disease [112, 113]. These studies highlight the relevance of the CD2:CD48 and CD2:CD58 pathways during ongoing autoimmunity, and their potential as therapeutic targets.…”

Section: Immunoregulatory Roles For Cd48 Determined By Studies In mentioning

confidence: 99%

Roles of CD48 in regulating immunity and tolerance

McArdel

Terhorst

Sharpe

2016

Clinical Immunology

164

134

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CD48, a member of the signaling lymphocyte activation molecule family, participates in adhesion and activation of immune cells. Although constitutively expressed on most hematopoietic cells, CD48 is upregulated on subsets of activated cells. CD48 can have activating roles on T cells, antigen presenting cells and granulocytes, by binding to CD2 or bacterial FimH, and through cell intrinsic effects. Interactions between CD48 and its high affinity ligand CD244 are more complex, with both stimulatory and inhibitory outcomes. CD244:CD48 interactions regulate target cell lysis by NK cells and CTLs, which are important for viral clearance and regulation of effector/memory T cell generation and survival. Here we review roles of CD48 in infection, tolerance, autoimmunity, and allergy, as well as the tools used to investigate this receptor. We discuss stimulatory and regulatory roles for CD48, its potential as a therapeutic target in human disease, and current challenges to investigation of this immunoregulatory receptor.

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“…The ability of compound 7 to bind to CD58 on Caco‐2 cells was evaluated using FITC‐CD58Ab in a competitive binding experiment and using flow cytometry and fluorescence plate reader assay in two different sets of experiments. Details of the procedures were published elsewhere . Briefly, Caco‐2 cells were distributed in seven different vials and 50 µL of FITC‐labeled anti‐CD58 with or without 100 µL of compound 7 was added at different concentrations.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of cell adhesion and immune responses in the mouse model of collagen‐induced arthritis with a peptidomimetic that blocks CD2‐CD58 interface interactions

et al. 2015

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CD2 and CD58 are two important co-stimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a β-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-γ) relative to control treatments. Compound 7 was found to be non-immunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA).

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Immunosuppression by Co‐stimulatory Molecules: Inhibition of CD2‐CD48/CD58 Interaction by Peptides from CD2 to Suppress Progression of Collagen‐induced Arthritis in Mice

Cited by 25 publications

References 58 publications

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein–Protein Interaction

Roles of CD48 in regulating immunity and tolerance

Inhibition of cell adhesion and immune responses in the mouse model of collagen‐induced arthritis with a peptidomimetic that blocks CD2‐CD58 interface interactions

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