Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism

Abstract

Immunostimulatory DNA sequences (ISS) contain unmethylated CpG dinucleotides within a defined motif. Immunization with ISS-based vaccines has been shown to induce high antigen-specific cytotoxic lymphocyte (CTL) activity and a Th1-biased immune response. We have developed a novel ISS-based vaccine composed of ovalbumin (OVA) chemically conjugated to ISS-oligodeoxynucleotide (ODN). Protein-ISS conjugate (PIC) is more potent in priming CTL activity and Th1-biased immunity than other ISS-based vaccines. Cytotoxic lymphocyte activation by ISS-ODN-based vaccines is preserved in both CD4-/- and MHC class II-/- gene-deficient animals. Furthermore, PIC provides protection against a lethal burden of OVA-expressing tumor cells in a CD8+ cell-dependent manner. These results demonstrate that PIC acts through two unique mechanisms: T-helper-independent activation of CTL and facilitation of exogenous antigen presentation on MHC class I. This technology may have clinical applications in cancer therapy and in stimulating host defense in AIDS and chronic immunosuppression.

APC Stimulated by CpG Oligodeoxynucleotide Enhance Activation of MHC Class I-Restricted T Cells

“…These results are not inconsistent with our results outlined above since nonspecific T cells could have contributed to the development of CTL in the mice immunized with CpG ODN plus SIINFEKL. Similarly, Cho et al (49) found CTL could be generated after immunization of MHC class II Ϫ/Ϫ and CD4 Ϫ/Ϫ mice with Ova-CpG ODN conjugates. Although our studies confirm that CpG ODN-treated DCs can activate CTL in the absence of T cell help, the addition of help greatly augmented CTL activation.…”

“…First, our studies and those by Vabulas et al (48) and Cho et al (49) evaluated different responses. We evaluated in vitro activation of class I-restricted cells by measuring proliferation and cytokine production of transgenic CD8 ϩ T cells soon after exposure of the cells to Ag-pulsed DCs.…”

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

“…The MHC class I peptides confer MUC1 specificity leading to the induction of CTL-mediated anti-tumor responses; the Hepatitis B core antigen-derived MHC class II pan T helper peptide was included to boost CD8 + anti-tumor responses [30,31]; CpG-ODN was included to promote DC activation via its interaction with Toll-like receptor (TLR)-9 [32,33] to enhance CTL responses, expansion and survival [33][34][35][36][37]. GM-CSF promotes antigen presentation and DC recruitment to vaccine sites [38][39][40][41] and is commonly used as a biological adjuvant in preclinical and clinical immunotherapy studies [42,43].…”

Immunostimulating capacities of stabilized RNA molecules

“…vaccines where the danger signals act as an adjuvant. Up to now, CpG-containing DNA has proven to be one of the strongest PAMP of interest for vaccination, rendering DC able to prime cytotoxic T cells even in the absence of CD4 help [8,9]. Synthetic DNA made of a stabilizing phosphorothioate backbone and containing at least one CpG motif can mimic bacterial DNA [10].…”