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Figure 5 Cytokines, chemokines, and costimulatory molecules as immune regulators. Cytokines, chemokines, and costimulatory molecules play critical roles in the immune and inflammatory responses. Based on their specific function in the immune system, these cytokines could be further grouped as proinflammatory, Th1, and Th2 cytokines. Along with costimulatory molecules and chemokines, these cytokines also play important roles in the activation and proliferation of T and B cells.

Figure 5 Cytokines, chemokines, and costimulatory molecules as immune regulators. Cytokines, chemokines, and costimulatory molecules play critical roles in the immune and inflammatory responses. Based on their specific function in the immune system, these cytokines could be further grouped as proinflammatory, Th1, and Th2 cytokines. Along with costimulatory molecules and chemokines, these cytokines also play important roles in the activation and proliferation of T and B cells.

immune responses may be a particularly important aspect of a multicomponent DNA vaccine strategy.

A. Cytokine Molecular Adjuvants

To focus the immune responses induced from DNA vaccines, we and others have investigated the codelivery of molecular adjuvants to modulate vaccine responses (65,127-135). We initially reported that coimmunization of GM-CSF cDNA with DNA vaccine constructs increases antigen-specific antibody and T helper cell proliferation responses, while coim-munization with IL-12 cDNA results in weaker antibody responses and enhanced T helper cell proliferation in mice (65,127). In addition, IL-12 coimmunization resulted in a significant enhancement of CTL responses. Importantly, we observed a significant enhancement of CTL response in vivo with the coadministration of murine IL-12 genes with 4 different HIV-1 DNA immunogens (gag/pol, envelope, vif, and nef), which were CD8+ T cell and MHC class I restricted. In contrast, almost no effect on CTL induction was observed with the genes for GM-CSF in these studies. Iwasaki et al. reported a similar finding using GM-CSF and IL-12 code-livery with DNA immunogen encoding for influenza NP.

More recently, we investigated the induction and regulation of immune responses from the codelivery of proinflam-matory cytokines (IL-1a, TNF-a, and TNF-p), Th1 cytokines (IL-2, IL-15, and IL-18), and Th2 cytokines (IL-4, IL-5, and IL-10) (128). We observed that some Th1, as well as Th2, cytokine genes increased the antibody response, specifically coinjection with IL-2, IL-4, IL-5, IL-10, and IL-18, all resulted in increased levels of antibodies. We also found that coinjec-

tion with TNF-a, TNF-p, IL-2, IL-10, and IL-18 resulted in a dramatic enhancement of T helper proliferation response, while coinjection with IL-5 and IL-15 resulted in a more moderate increase in T helper proliferation. Furthermore, among all coinjection combinations, we found that only TNF-a and IL-15 coinjections resulted in a high level of CTL enhancement similar to that of IL-12 coinjection. Coinjection with TNF-p, IL-2, and IL-18 resulted in a more moderate increase in CTL response over those groups immunized with only DNA immunogen. As observed with IL-12 coinjection, the enhancement of CTL responses observed from the coinjections with TNF-a and IL-15 were restricted by MHC class I and CD8 + T cell dependent.

We also investigated whether the Th1- or Th2-type immune responses are more important for protection from HSV-2 infection (136). We codelivered DNA expression construct encoding for HSV-2 gD protein with the gene plasmids encoding for Th1-type (IL-2, IL-12, IL-15, IL-18) and Th2-type (IL-4, IL-10) cytokines in an effort to drive immunity induced by vaccination. We then analyzed the vaccine modulatory effects on resulting immune phenotype and on the mortality and morbidity of the immunized animals, following HSV lethal challenge (Fig. 6). We observed Th1 cytokine gene coadmin-istration not only enhanced survival rate, but also reduced the frequency and severity of herpetic lesions following intravaginal HSV challenge. However, coinjection with Th2 cytokine genes increased the rate of mortality and morbidity of the challenged mice. Again, among the Th1-type cytokine genes tested, IL-12 was particularly a potent adjuvant for the gD DNA vaccination, resulting in increased survival and decreased animal morbidity.

B. Chemokine Molecular Adjuvants

Similar to cytokine gene codelivery, we found that the coim-munization with chemokine genes along with DNA immuno-

gen constructs can modulate the direction and magnitude of induced immune responses (130). We observed that coimmun-ization with IL-8 and MIP-1a genes increased the antibody response in a similar manner to IL-4 or GM-CSF coimmuniza-tion. We also found that coinjection with IL-8 and RANTES resulted in a dramatic enhancement of T helper proliferation response. Among all coinjection combinations, we found that RANTES and MCP-1 coinjections resulted in a high level of CTL enhancement, almost as significant as IL-12, a potent CTL inducer for DNA vaccines. In addition, there is evidence that suggests some chemokine adjuvanted vaccines require a direct fusion of the immunogen with the chemokine. For instance, immunization against HIV gp120 with monocyte chemoattractant protein-3 (MCP-3/CCL7) or macrophage-derived chemokine (MDC/CCL22) requires the direct fusion of the 2 for effective immune response induction. Accordingly, coimmunization revealed minimal immune enhancement (137). Therefore, the use of these chemokine vaccines could be particularly important as HIV vaccine modulators of P-chemokines. In this regard, we observed that p-chemokines as vaccine adjuvants augmented p-chemokine production in a vaccine antigen-specific manner. This aspect could be especially important for a development of a vaccine that modulates the earliest aspects of the inflammatory response.

C. Costimulatory Molecule Molecular Adjuvants

Professional APCs initiate T cell activation through binding of antigenic peptide-MHC complexes to specific T cell receptor molecules. In addition, the APCs provide critical costimula-tory signals to T cells, which are required for the clonal expansion and differentiation of T cells. Among different costimula-tory molecules, B7 molecules (CD80 and CD86) have been

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