Τίτλος:
Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2/neu epitopes
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background: Active 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 proTα(100-109) induce the maturation of human DCs in vitro. The aim of this study was to investigate whether proTα- or proTα(100-109)-matured DCs are functionally competent and to provide preliminary evidence for the mode of action of these agents.Results: Monocyte-derived DCs matured in vitro with proTα or proTα(100-109) express co-stimulatory molecules and secrete pro-inflammatory cytokines. ProTα- and proTα(100-109)-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 proTα(100-109) 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.Conclusions: Our results suggest that proTα and proTα(100-109) induce both the maturation and the T cell stimulatory capacity of DCs. Although further studies are needed, evidence for a possible proTα and proTα(100-109) 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. © 2013 Ioannou et al.; licensee BioMed Central Ltd.
Συγγραφείς:
Ioannou, K.
Derhovanessian, E.
Tsakiri, E.
Samara, P.
Kalbacher, H.
Voelter, W.
Trougakos, I.P.
Pawelec, G.
Tsitsilonis, O.E.
Περιοδικό:
BMC Immunology
Λέξεις-κλειδιά:
epidermal growth factor receptor 2; epitope; myeloid differentiation factor 88; protein precursor; prothymosin alpha; prothymosin alpha derived peptide; tirapazamine; toll like receptor 4; unclassified drug, article; CD4+ T lymphocyte; CD8+ T lymphocyte; cell maturation; cellular immunity; controlled study; cytokine production; cytokine release; dendritic cell; human; human cell; lymphocyte proliferation; phenotype; protein protein interaction; Th1 cell, Adaptor Proteins, Vesicular Transport; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines; Dendritic Cells; Epitopes; Flow Cytometry; Humans; Immunoblotting; Immunotherapy, Adoptive; Lymphocyte Activation; Membrane Glycoproteins; Myeloid Differentiation Factor 88; Peptides; Protein Precursors; Receptor, erbB-2; Receptors, Interleukin-1; T-Lymphocytes, Cytotoxic; Th1 Cells; Thymosin; Toll-Like Receptor 4
DOI:
10.1186/1471-2172-14-43
