Rational design of biologically active peptides: inhibition of T cell activation through interference with CD4 function.
In our laboratory we generated one synthetic cyclic peptide (Pep4) and tested it in human mitogen stimulation assays (MSA) and mixed lymphocytes reactions (MLR) generating dose-response curves showing a dose-dependent inhibition of MSA up to 80% and MLR up to 98%. MSA and MLR were repeated after pre incubation of the Pep4 with each separate responder cell subset and subsequent reconstitution: these experiments showed inhibition only when the peptide was present in culture. Pep4 showed species specificity since it was ineffective in inhibiting rat MLR. Combination effect analysis with Pep4 and cyclosporine showed a combination index > 1. This rationally designed peptide (Pep4) shows powerful inhibition of human T cell activation and, although the exact mechanism is still undefined, it seems to exert its major action on the T cell surface, interfering with co receptor interaction and disrupting the same activation signal pathway inhibited by cyclosporine A.
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Vascular Surgery Department, CNR Centro di Fisiopatologia dello Shock, and Istituto Dermopatico dell'Immacolata IRCCS Rome, Italy.
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D000818:Animals; D015704:CD4 Antigens / Q000187:drug effects / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D010455:Peptides; D010456:Peptides, Cyclic; D016572:Cyclosporine