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Chapter category: Vaccines

Activation of the Innate Immune System by DNA Vaccines

Chapter authors:
Julie Fitzgerald and Hildegund C. J. Ertl

DNAvaccines were discovered serendipitously by gene therapists attempting to replace missing or faulty genes with bacterial expression vectors. The transgene product was found to elicit an immune response that rapidly eliminated the transduced cells¹ reducing the attractiveness of this approach for gene replacement therapy while opening the field of DNA vaccinology. DNA vaccines were initially injected intramuscularly where they were shown to transduce local muscle cells.² This added further to the puzzle of their immunogenicity. Why would a small piece of circular DNA injected in saline upon uptake by cells not considered professional antigen presenting cells induce both T and B cells to the encoded gene product, when even large doses of foreign protein require addition of an adjuvant to induce a robust immune response? The initial suspicion that the immunogenicity of DNA vaccines was linked to their contamination with trace amounts of lipopolysaccharides from the bacteria used to propagate the DNA vaccines was rapidly dismissed experimentally. Bacterial DNA had been known prior to the era of DNA vaccines as an activator of B and NK cells and as potential tumor therapeutics.³ This effect could be mimicked by synthetic oligodeoxinucleotides (ODNs) with self‑complemtentary palindromic sequences.⁴ Eventually it was appreciated that such palindromic sequences that are unmethylated CpG motifs common in bacterial but not mammalian genome were crucial for the immunogenicity of DNA vaccines by providing inflammatory signals to the innate immune system.

The innate immune system, our first line of defense against pathogenic microorganisms, was previously thought of as a group of entirely nonspecific cells, which phagocytose foreign together with host‑derived material at random. Now it is known that the cells of the innate immune system carry receptors called Toll‑like receptors (TLRs), which are evolutionary highly conserved germ‑line encoded receptors that recognize specific traits of microorganisms and then orchestrate an adaptive immune response most suited to combat the invading pathogen.^5,6 TLRs were named for their similarity to the Toll protein found in Drosophila where it plays a role in defense against fungal infections and dorsoventral patterning of the embryo.^6‑9 According to phylogenetic analysis, the ancestral prevertebrate TLR evolved approximately 500 million years ago.¹⁰

Unlike the receptors of the adaptive immune system, TLRs are nonclonal receptors. They are part of a family of pattern recognition receptors (PRRs) which recognize certain unique motifs conserved among microbes called pathogen‑associated molecular patterns (PAMPs).^5,11 This specificity allows the innate immune system to distinguish microbial antigens from each other and from part of the nonthreatening antigens from the host cells or other benign or even essential foreign materials such as food. An adaptive immune response is initiated by antigen displayed on professional antigen presenting cells (APCs) which are mature dendritic cells. Such dendritic cells are dispersed at an immature stage throughout an organism. Immature dendritic cells take up antigen but they are ill suited to present such antigen to naÔve T or B cells. Upon receiving a maturation signal, dendritic cells undergo a number of phenotypic and functional changes and migrate to the T cell rich areas of draining lymph nodes where they can now activate an adaptive immune response. Dendritic cells come in different shapes and forms and are currently roughly divided into type 1 and type 2 dendritic cells, which have distinct albeit overlapping functions. In humans, type 1 dendritic cells upon activation secrete IL‑12 thus sponsoring activation of type 1 T helper cell responses.¹² Type 2 dendritic cells produce markedly lower amounts of IL‑12 and favor activation of type 2 T helper cells.¹² Type 1 and 2 dendritic cells express unique patterns of TLRs as was shown for human dendritic cells: type 1 dendritic cells express high levels of TLR‑1, 2, 3, low levels of TLR‑5, 6, 8 and 10 and no TLR‑4, 7 and 9 while type 2 dendritic cells in contrast express high levels of transcript for TLR‑7 and 9, low levels of TLR‑1, 6 and 10 but no TLR‑2, 3, 4, 5 or 8.¹³ Different types of dendritic cells thus become matured by different microbes. This further allows the innate immune system to control which type of an adaptive immune response is generated against a pathogen.

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