TY - JOUR
TI - Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2/neu epitopes
AU - Ioannou, K.
AU - Derhovanessian, E.
AU - Tsakiri, E.
AU - Samara, P.
AU - Kalbacher, H.
AU - Voelter, W.
AU - Trougakos, I.P.
AU - Pawelec, G.
AU - Tsitsilonis, O.E.
JO - BMC Immunology
PY - 2013
VL - 14
TODO - 1
SP - null
PB - 
SN - 1471-2172
TODO - 10.1186/1471-2172-14-43
TODO - 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
TODO - 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.
ER -