DNA–based immunization by in vivo transfection of dendritic cells

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Abstract

Delivery of antigen in a manner that induces effective, antigen-specific immunity is a critical challenge in vaccine design. Optimal antigen presentation is mediated by professional antigen-presenting cells (APCs) capable of taking up, processing and presenting antigen to T cells in the context of costimulatory signals required for T-cell activation. Developing immunization strategies to optimize antigen presentation by dendritic cells, the most potent APCs, is a rational approach to vaccine design. Here we show that cutaneous genetic immunization with naked DNA results in potent, antigen-specific, cytotoxic T lymphocyte-mediated protective tumor immunity. This method of immunization results in the transfection of skin-derived dendritic cells, which localize in the draining lymph nodes. These observations provide a basis for further development of DNA-based vaccines and demonstrate the feasibility of genetically engineering dendritic cells in vivo.

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Most cited references 25

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Genetic immunization is a simple method for eliciting an immune response.

D C Tang, M. DeVit, S Johnston (1992)

To produce an immune reaction against a foreign protein usually requires purification of that protein, which is then injected into an animal. The isolation of enough pure protein is time-consuming and sometimes difficult. Here we report that such a response can also be elicited by introducing the gene encoding a protein directly into the skin of mice. This is achieved using a hand-held form of the biolistic system which can propel DNA-coated gold microprojectiles directly into cells in the living animal. Genetic immunization may be time- and labour-saving in producing antibodies and may offer a unique method for vaccination.

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Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens.

A Huang, P Golumbek, M. Ahmadzadeh … (1994)

Many tumors express tumor-specific antigens capable of being presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Antigen presentation models predict that the tumor cell itself should present these antigens to T cells. However, when conditions for the priming of tumor-specific responses were examined in mice, no detectable presentation of MHC class I-restricted tumor antigens by the tumor itself was found. Rather, tumor antigens were exclusively presented by host bone marrow-derived cells. Thus, MHC class I-restricted antigens are efficiently transferred in vivo to bone marrow-derived antigen-presenting cells, which suggests that human leukocyte antigen matching may be less critical in the application of tumor vaccines than previously thought.

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Introduction of soluble protein into the class I pathway of antigen processing and presentation.

M Moore, F R Carbone, M J Bevan (1988)

In order to investigate how peptides associate with class I major histocompatibility complex (MHC) glycoproteins intracellularly, we generated cytotoxic T lymphocytes (CTL) specific for a readily available soluble protein in association with class I. C57BL/6 (H-2b) mice immunized against a syngeneic tumor cell transfected with chicken ovalbumin (OVA) cDNA gave rise to H-2Kb-restricted CTL specific for the OVA258-276 peptide. This synthetic peptide and CNBr fragments of OVA (242-285 and 242-273) were able to target H-2b cells for lysis by the CTL in a 3 hr assay. Cells incubated with native OVA for up to 24 hr did not become sensitized for recognition and lysis. However, when OVA was introduced directly into the cytoplasm of cells by the osmotic lysis of pinosomes, the Kb restricted determinant formed readily.