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

Abstract

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.

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

“…Furthermore, the SCHOOL model explains for the first time the molecular mechanisms of ligand-independent inhibition of another MIRR, the T cell receptor (TCR), by using a short synthetic peptide (SCHOOL peptide) corresponding to the transmembrane sequence of TCR-α chain [51]. As demonstrated in cell, animal, and preliminary human studies, inhibitory TCR SCHOOL peptides can represent a novel approach to treat TCR-mediated disorders [52]. Another exemplary member of the MIRR family is glycoprotein VI (GPVI).…”

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“…In our experiments, we used T cells either enriched by nylon wool passage (purity of 80 -85%) or sorted by FACSCalibur (Ͼ98% pure). Numerous reports have described T cell-mediated suppression of cellular immune responses (43)(44)(45)(46), but a uniform phenotype of the pertinent T suppressor cells has not emerged. The various T cell subsets include CD4 ϩ CD25 ϩ CTLA-4 ϩ cells (47,48) and CD8 ϩ cells (32,49).…”

Novel Mechanistic Insights into Viral Modulation of Immune Receptor Signaling

“…Interestingly, T cell activation via anti-CD3 antibodies is not affected by this peptide ( Table 1). As shown, TCR CP might be a proper treatment for human T cell-mediated dermatoses substituting for corticosteroids [17,18]. However, despite extensive studies [2,[17][18][19][20][21][22][23][24][25][26][27][28], the mode of action of this clinically relevant peptide was not explained until 2004 when the SCHOOL model was first introduced [6].…”