Minh-Duc Nguyen

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

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.

Immunostimulatory DNA-Based Vaccines Elicit Multifaceted Immune Responses Against HIV at Systemic and Mucosal Sites

Immunostimulatory DNA sequences (ISS, also known as CpG motifs) are pathogen-associated molecular patterns that are potent stimulators of innate immunity. We tested the ability of ISS to act as an immunostimulatory pathogen-associated molecular pattern in a model HIV vaccine using gp120 envelope protein as the Ag. Mice immunized with gp120 and ISS, or a gp120:ISS conjugate, developed gp120-specific immune responses which included: 1) Ab production; 2) a Th1-biased cytokine response; 3) the secretion of β-chemokines, which are known to inhibit the use of the CCR5 coreceptor by HIV; 4) CTL activity; 5) mucosal immune responses; and 6) CD8 T cell responses that were independent of CD4 T cell help. Based on these results, ISS-based immunization holds promise for the development of an effective preventive and therapeutic HIV vaccine.

DNA‐based vaccination for the treatment of food allergy

At present, avoidance is the only therapeutic option available for individuals with food allergies. However, studies suggest that DNA‐based vaccination might be an effective therapeutic option for the reversal of allergic hypersensitivities, including allergies to foods. Because severe anaphylactic reactions represent a life‐threatening risk for individuals with food allergies, we and others have evaluated the effectiveness of DNA‐based vaccination for the prevention of anaphylactic hypersensitivity in murine models. Our investigations demonstrated that primary gene and protein/immunostimulatory sequence oligodeoxynucleotide (ISS‐ODN) vaccination of subsequently Th2‐sensitized mice reduced the risk of death after anaphylactic challenge, significantly. In addition, gene and protein/ISS‐ODN vaccination reduced post challenge plasma histamine levels. Analysis of the immune profiles of mice receiving DNA‐based vaccines showed that both gene and protein/ISS‐ODN vaccination effectively prevented the development of Th2‐biased immune profiles after sensitization. In contrast, vaccination with protein alone, the experimental equivalent of the traditional protein‐based immunotherapy (IT) reagents used in clinical practice provided no protection from anaphylaxis, nor did it prevent the development of a Th2‐biased immune profile after allergen sensitization. These studies justify continued optimism in the potential of DNA‐based vaccination for the desensitization of food allergic individuals.