Therapeutic application of T cell receptor mimic peptides or cDNA in the treatment of T cell-mediated skin diseases

Göllner, GP; Müller, Gabriele; Alt, Ruth; Knop, Jürgen; Enk, A.

doi:10.1038/sj.gt.3301183

Cited by 38 publications

(28 citation statements)

References 17 publications

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“…More recently we have shown that CP and its lipid conjugates have a comparable effect to cyclosporine in reducing inflammation in the adjuvant-induced rat arthritis model. 2 Gollner et al (11) have used CP in humans and in their few cases examined noted that it was effective in the treatment of autoimmune skin conditions. More recently Mahnke et al (12) have genetically engineered dendritic cells to secrete the peptide and reduce inflammation in a T cell-dependent animal disease model, experimental allergic encephalomyelitis.…”

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confidence: 99%

T Cell Antigen Receptor Peptide-Lipid Membrane Interactions Using Surface Plasmon Resonance

Bender

Ali

Amon

et al. 2004

Journal of Biological Chemistry

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This study examines the binding properties of a new class of immunomodulating peptides derived from the transmembrane region of the T cell antigen receptor, on model membranes using surface plasmon resonance. The di-basic "core" peptide was found to bind to both zwitterionic and anionic model membranes as well as to a T cell membrane preparation. By contrast, switching one or both of the basic residues to acidic residues led to a complete loss of binding to model membranes. In addition, the position of the charged amino acids in the sequence, the number of hydrophobic amino acids between the charged residues, and substitution of one or both basic to neutral amino acids were found to effect binding. These results when compared with in vitro T cell stimulation assays and in vivo adjuvant-induced arthritis models, showed very close correlation and confirmed the findings that amino acid charge and location may have a role in peptide activity. These initial biophysical peptide-membrane interactions are critically important and correlate well with the subsequent cellular expression and biological effect of these hydrophobic peptides. Targeting and understanding the biophysical interactions between peptides and membranes at their site of action is paramount to the description of cell function and drug design.T cells constitute an important component of our immune system and are concerned with immune surveillance and antigen recognition. Whereas this is normally a beneficial, protective effect, recognition of "self-antigens" under altered pathological states leads to autoimmune disease with deleterious consequences. The T cell antigen receptor (TCR) 1 is a cell surface multisubunit protein complex present only on T cells and involved with antigen recognition and subsequent T cell activation. The TCR consists of two clonotypic chains (TCR-␣ and -␤) that are noncovalently linked to CD3-⑀, -␥, -␦, and -/ invariant proteins. Two important structural features common to these chains is the presence of a single transmembrane spanning domain and the presence of charged amino acid(s) within their predicted transmembrane region. The invariant chains have a single negative charge and TCR-␣ and -␤ have two and one positive charges, respectively. These charged amino acids influence the intracellular fate of these proteins and are critical for TCR assembly (1, 2). Following TCR cell surface expression a key event in initiating antigen-induced signal transduction is the formation of higher order oligomerization complexes between TCR, co-receptors, and accessory molecules at the cell membrane. This protein-protein-lipid interface allows a number of biochemical events to proceed rapidly commencing with tyrosine or serine/threonine phosphorylation of the TCR chains (3) that subsequently translates into T cell activation and cytokine production. The ability to inhibit pathogenic T cells by blocking the TCR by hydrophobic transmembrane-derived peptides has been the focus of our research for a number of years (4 -8).We have previously ide...

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confidence: 99%

T Cell Antigen Receptor Peptide-Lipid Membrane Interactions Using Surface Plasmon Resonance

Bender

Ali

Amon

et al. 2004

Journal of Biological Chemistry

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“…13,14 Application of a 8 aa peptide sequence corresponding to the transmembrane region of T cell receptor alpha chain or DNA encoding the above peptide on to the surface of the skin resulted in local immunosuppression. 15 Based on these reports and given the fact that Sm16 has potential anti-inflammatory functions in vitro and in vivo, 6,7 we wanted to evaluate whether gene coding for Sm16 could be used similarly to alleviate an inflammatory response in the skin.…”

Section: Shown By a Reduction In Cutaneous Edema Decrease In Neutropmentioning

confidence: 99%

Suppression of cutaneous inflammation by intradermal gene delivery

Rao

Kalyanasundaram

2002

Gene Ther

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“…Error bars indicate standard error (n = 7, p < 0.005). Reproduced with permission from Göllner et al [7]. …”

Section: Topical Application Of Mimic Peptide Suppresses Skin Immune mentioning

confidence: 99%

“…To avoid systemic toxicity, but still achieve an immunosuppressive effect, we decided to investigate the effect of topical application of the mimic peptide on T-cell-mediated immune responses in skin [7]. Allergic contact dermatitis (ACD) is an example of a T-cell-mediated delayed-type hypersensitivity (DTH) [8]skin reaction.…”

Section: Topical Application Of Mimic Peptide Suppresses Skin Immune mentioning

confidence: 99%

T Cell Receptor Mimic Peptidesand Their Potential Application in T-Cell-Mediated Diseas e

Enk¹,

Knop²

2000

Int Arch Allergy Immunol

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Background: A T cell receptor (TCR) peptide was designed that mimics the intramembranous amino acid sequence of the TCR chain. Prior studies had shown that this mimic peptide would inhibit TCR signaling. This study was designed to investigate the use of this mimic peptide for the treatment of T-cell-mediated skin diseases. Methods: Synthesized mimic peptides were first tested for their T-cell-inhibitory effect in proliferation assays. Afterwards, mimic peptides were applied to murine ear skin prior to application of a contact allergen and tested for their inhibitory effect in the model of murine allergic contact sensitivity. The effect of epicutaneous treatment with the peptide was also tested on patients with T-cell-mediated skin disease. Results: Mimic peptide potently inhibited proliferation of CD4+ and CD8+ T cells when added to allogeneic proliferation assays using dendritic cells as antigen-presenting cells (APCs). Suppression of the proliferative capacity could be overcome by addition of an anti-CD3 monoclonal antibody. When applied to murine ear skin prior to application of a contact allergen, mimic peptide efficiently blocked ear swelling responses in mice. In humans, application of mimic peptide for the treatment of various diseases resulted in amelioration or even cure in patients suffering from atopic dermatitis, psoriasis or lichen planus. Conclusions: TCR mimic peptide efficiently abrogates T-cell-mediated immune responses in mice and man in vitro and in vivo. The potential immunosuppressive effect of the drug is discussed.

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Therapeutic application of T cell receptor mimic peptides or cDNA in the treatment of T cell-mediated skin diseases

Cited by 38 publications

References 17 publications

T Cell Antigen Receptor Peptide-Lipid Membrane Interactions Using Surface Plasmon Resonance

T Cell Antigen Receptor Peptide-Lipid Membrane Interactions Using Surface Plasmon Resonance

Suppression of cutaneous inflammation by intradermal gene delivery

T Cell Receptor Mimic Peptidesand Their Potential Application in T-Cell-Mediated Diseas e

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