Enhanced major histocompatibility complex class I-dependent presentation of antigens modified with cationic and fusogenic peptides

Laus, Reiner; Graddis, Thomas J.; Hakim, I.; Vidovic, Damir

doi:10.1038/82377

Cited by 33 publications

(32 citation statements)

References 18 publications

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“…Treatment of accessory cells (including DC) with native OVA modified with positively charged peptides enabled them to stimulate MHC class I-restricted OVA-specific T cell hybridomas in vitro and to induce at least limited CTL activity in vivo (32). This approach does not appear to afford advantages over the one that we describe and is feasible only if purified Ags are available.…”

Section: Discussionmentioning

confidence: 92%

Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity

Shibagaki

Udey

2002

The Journal of Immunology

124

106

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Dendritic cell (DC)-based vaccines are being developed for treatment of patients with cancer, in part because DC are potent inducers of CD8+ CTL. DC MHC class I:antigenic peptide complexes that are required for CTL elicitation are most often generated by incubating DC with peptides or by transfecting (or transducing) DC with cDNAs (or viral vectors) that encode protein Ags. The former approach is feasible when MHC class I Ags and relevant peptides are known. The latter approach may be hampered by inefficient DC transfection (transduction) and/or difficulties associated with preparation and use of viral vectors. Herein we demonstrate that a bacterial recombinant model tumor-associated Ag (OVA) that contains the HIV TAT protein transduction domain (PTD) was readily engineered and purified, efficiently transduced murine lymphocytes and DC, and was processed by proteasomes for MHC class I-restricted presentation to CTL. In addition, PTD-containing rOVA was processed and presented by DC to CD4 T cells as efficiently as native OVA or rOVA lacking the PTD. PTD-OVA-transduced DC induced CTL in vivo in a Th cell-independent fashion and vaccinated against OVA-expressing tumors. In contrast, rOVA lacking the PTD did not enter the DC MHC class I presentation pathway and DC treated with this protein did not prime OVA-specific CTL in vivo. Treatment of mice harboring clinically apparent OVA-expressing tumors with PTD-OVA-transduced DC resulted in tumor regression in some animals. This straightforward vaccination strategy may translate into DC-based treatments for patients with cancer and other serious diseases.

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Section: Discussionmentioning

confidence: 92%

Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity

Shibagaki

Udey

2002

The Journal of Immunology

124

106

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“…This process, called cross-presentation (22), may lead to the induction of Ag-specific CD8 ϩ CTL. To enhance crosspresentation, several strategies have been applied, including the use of specific carrier molecules such as gp96 (23), cationic and fusogenic peptides (24), and outer membrane protein A from Klebsiella pneumoniae (25). Various methods have been employed to make FP, such as chemical cross-linking, E. coli or baculovirus expression systems, and artificial peptide synthesis.…”

Section: Discussionmentioning

confidence: 99%

Induction of Antigen-Specific CTL by Recombinant HIV Trans-Activating Fusion Protein-Pulsed Human Monocyte-Derived Dendritic Cells

Tanaka

Dowdy

Linehan

et al. 2003

The Journal of Immunology

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Several systems have been tested for introduction of Ags into human dendritic cells (DC). Most of them to date, however, are complex and possess limited efficiency. Recent advances in HIV trans-activating (TAT) fusion protein technology permit extremely high transduction efficiencies for a majority of mammalian cell types. Here we report our attempts to develop a simple, but highly efficient, protocol for loading of antigenic protein into DC using TAT fusion technology. A TAT-minigene fusion protein was generated, encoding both the HLA-A2-restricted influenza matrix protein-derived epitope (GILVFTFTL, Flu-M1) and a melanoma Ag gp100-derived modified epitope (YLEPGPVTV, G9(280)-9V). In addition, both a TAT-Her2/neu extracellular domain (ECD) fusion protein and a TAT-green fluorescence protein fusion protein were generated. Over 95% of DC stained positively for TAT-green fluorescence protein within 20 min of coculture. DC treated with TAT-minigene were efficiently recognized by both Flu-M1 and G9(280)-9V-specific T cells in cytotoxicity assays and IFN-gamma ELISPOT assays. In contrast, DC pulsed with minigene fusion protein lacking TAT were either poorly recognized or not recognized by the T cells. DC pulsed with TAT-minigene also efficiently induced Flu-M1-specific T cells from naive lymphocytes. Similarly, DC treated with TAT-Her2/neu ECD stimulated patient-derived lymphocytes that specifically recognized Her2/neu(+) ovarian and breast cancer cell lines. The CTL induced by TAT-Her2/neu ECD-pulsed DC specifically recognized the Her2/neu ECD-derived immunogenic peptide E75 (KIFGSLAFL). Our data suggest that TAT fusion proteins efficiently transduce DC and induce Ag-specific T cells. This could prove to be a useful method for treatment of infectious diseases and cancer.

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“…These molecules can deliver cargos fused or associated to them into the cytoplasm of cells and therefore make them directly accessible to the MHC class I presentation pathway [20][21][22]. APCs loaded with cell permeable peptides have been successfully used in vitro and in vivo for induction of CD8+ T-cell-mediated immune responses [21][22][23][24][25][26]. However, at present there is little information available whether CPP can be used to improve the immunogenicity and efficacy of complete proteins when CPP fusion proteins are administered directly as vaccines [27].…”

mentioning

confidence: 99%

The translocation motif of hepatitis B virus improves protein vaccination

Bleifuß

Kammertoens

Hutloff

et al. 2006

Cell. Mol. Life Sci.

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Cell-penetrating peptides (CPPs) have been shown to improve antigen loading of dendritic cell vaccines. Here we asked whether fusion of a CPP to a protein improves its immunogenicity when this fusion protein is directly applied as vaccine. We used the cell-penetrating translocation motif (TLM) derived from the hepatitis B virus, because no size limitation of cargos has been observed. Increased immunogenicity was observed when TLM was fused to ovalbumin (TLM-ova). TLM-ova was found to be superior to ova in inducing proliferation and cytotoxicity of ova-specific CD8+ T cells in vitro and in vivo. Using ovalbumin-expressing thymoma cells (EG7-ova), an improved anti-tumor immune response was observed for TLM-ova vaccination versus vaccination with ova. Moreover, TLM-ova vaccination induced a higher titer of anti-ovalbumin IgG2a antibodies compared to ova. These data demonstrate that CPP-protein vaccines can improve cellular as well as humoral immune responses.

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Enhanced major histocompatibility complex class I-dependent presentation of antigens modified with cationic and fusogenic peptides

Cited by 33 publications

References 18 publications

Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity

Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity

Induction of Antigen-Specific CTL by Recombinant HIV Trans-Activating Fusion Protein-Pulsed Human Monocyte-Derived Dendritic Cells

The translocation motif of hepatitis B virus improves protein vaccination

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