Acute Cytokine Response to Systemic Adenoviral Vectors in Mice Is Mediated by Dendritic Cells and Macrophages

Abstract

We investigated the cellular basis for secretion of inflammatory cytokines in mice following intravenous administration of adenoviral vectors (Ad). Serum inflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-alpha (TNF-alpha) were detected as early as 6 h following intravenous injection of Ad-expressing Escherichia coli beta-galactosidase (Ad-lacZ). Ad-lacZ readily accumulated in the splenic marginal zone 1 h after intravenous infusion, where both dendritic cells (DCs) and macrophages were transduced and activated within 6 h. Flow cytometric analyses showed that the expression of Ia and CD86 antigens was markedly enhanced on splenic DCs indicating their activation in vivo by Ad-lacZ. Upon ex vivo culture, these early-activated splenic DCs spontaneously produced high levels of IL-6 and IL-12. By contrast, activated splenic macrophages spontaneously secreted only IL-6. Elimination of tissue macrophages and splenic DCs in vivo considerably reduced the early release of IL-12, IL-6, and TNF-alpha and significantly blocked the specific cellular immune response to Ad and the transgene product in vivo. Our findings indicate that preferential activation of DCs and macrophages may account for Ad-triggered acute inflammatory response in vivo in mice. Moreover, DCs and macrophages may play different roles in this process in terms of their abilities to produce distinct patterns of inflammatory cytokines.

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

“…In vivo transduction of dendritic cells and macrophages by recombinant adenovirus has been previously described after i.v. 13,15 or i.m. injection.…”

“…gene transfer could be due to the well-known migration of donor DCs from the heart into the spleen and not mesenteric lymph nodes 18,19 after AdHO-1 transduction or due to the migration of adenoviral particles from the heart to the spleen where they could transduce recipient DCs or macrophages. 13 Finally, the inhibition of MLRs by non-T cells suggests that spleen APCs could mediate this inhibition.…”

“…18,19 In keeping with this anatomical distribution, AdHO-1 probably concentrated in the spleen and not in mesenteric lymph nodes. 13,15 Alternatively, activated tolerogenic T cells may circulate through the spleen but may not be found in lymph nodes, since activated T cells lose their expression of CD62L and gain the expression of VLA4, 22 resulting in a diminished capacity to home to lymph nodes and an increased capacity to home to the graft.…”

“…administration of AdHO-1 significantly increased allograft survival (472.2713.6, n ¼ 8) compared to both control groups, and 62.5% of the cardiac grafts showed long-term survival ( Figure 1). Lastly, AdHO-1 administration i.v., which results in the majority of viruses being trapped and expressed within the liver, lungs and spleen, 13 also significantly delayed heart allograft rejection (495.674.4, n ¼ 5) compared to both control groups, and 80% of the allografts displayed long-term survival (Figure 1). Allograft survival in the groups injected with AdHO-1 i.m.…”

Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response

“…However, it has been suggested that preferential activation of macrophages and dendritic cells by adenovirus leads to acute inflammatory response in mice. 48 There is a need to study the role of alginate microparticles in modulating immune response through macrophages and dendritic cells. It is believed that adenovirus will be released from microparticles slowly over a period, thereby reducing the toxicity mediated by the activation of macrophages and dendritic cells by adenovirus.…”