Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2-neu epitopesReportar como inadecuado




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BMC Immunology

, 14:43

Cellular immunology and immune regulation

Abstract

BackgroundActive cancer immunotherapies are beginning to yield clinical benefit, especially those using peptide-pulsed dendritic cells DCs. Different adjuvants, including Toll-like receptor TLR agonists, commonly co-administered to cancer patients as part of a DC-based vaccine, are being widely tested in the clinical setting. However, endogenous DCs in tumor-bearing individuals are often dysfunctional, suggesting that ex vivo educated DCs might be superior inducers of anti-tumor immune responses. We have previously shown that prothymosin alpha proTα and its immunoreactive decapeptide proTα100–109 induce the maturation of human DCs in vitro. The aim of this study was to investigate whether proTα- or proTα100–109-matured DCs are functionally competent and to provide preliminary evidence for the mode of action of these agents.

ResultsMonocyte-derived DCs matured in vitro with proTα or proTα100–109 express co-stimulatory molecules and secrete pro-inflammatory cytokines. ProTα- and proTα100–109-matured DCs pulsed with HER-2-neu peptides induce TH1-type immune responses, prime autologous naïve CD8-positive + T cells to lyse targets expressing the HER-2-neu epitopes and to express a polyfunctional profile, and stimulate CD4+ T cell proliferation in an HER-2-neu peptide-dependent manner. DC maturation induced by proTα and proTα100–109 is likely mediated via TLR-4, as shown by assessing TLR-4 surface expression and the levels of the intracellular adaptor molecules TIRAP, MyD88 and TRIF.

ConclusionsOur results suggest that proTα and proTα100–109 induce both the maturation and the T cell stimulatory capacity of DCs. Although further studies are needed, evidence for a possible proTα and proTα100–109 interaction with TLR-4 is provided. The initial hypothesis that proTα and the proTα-derived immunoactive decapeptide act as -alarmins-, provides a rationale for their eventual use as adjuvants in DC-based anti-cancer immunotherapy.

KeywordsProthymosin alpha Immunoreactive peptide Dendritic cells TH1 immune responses TLR-4 Adjuvant HER-2-neu peptides AbbreviationsHMGB1High mobility group box 1

HSPHeat shock protein

MFIMean fluorescence intensity

proTαProthymosin alpha

TLRToll-like receptor.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2172-14-43 contains supplementary material, which is available to authorized users.

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Autor: Kyriaki Ioannou - Evelyna Derhovanessian - Eleni Tsakiri - Pinelopi Samara - Hubert Kalbacher - Wolfgang Voelter - Ioannis 

Fuente: https://link.springer.com/







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