Dendritic cells transduced with an adenovirus vector encoding interleukin-12 are a potent vaccine for invasive pulmonary aspergillosis

Abstract

Invasive pulmonary aspergillosis (IPA) is a common and devastating pneumonia. We developed a novel antiinfective vaccine that couples the potent Ag-presenting capacity of dendritic cells (DCs) with paracrine delivery of interleukin-12 (IL-12) to local immune response sites. Our results showed that DCs engulfed Aspergillus conidia through coiling phagocytosis. Transfection of DCs with adenovirus encoding the cDNA of IL-12 did not affect their morphology and capacity to engulf conidia. The transduced DCs secreted IL-12, which was biologically active, to induce the production of gamma interferon (IFN-g) from spleen cells. Adoptive transfer of DCs pulsed with heat-inactivated Aspergillus fumigatus (HAF) to naïve mice induced the Ag-specific production of IFN-g; the transduced HAF-pulsed DCs augmented this immune response further. Animals receiving HAF-pulsed DCs had lower fungal burdens, a more than three-fold higher survival rate at day 3. This protection was associated with a pronounced enhancement in the Aspergillus-specific IFN-g response. IL-12-engineered DCs augmented this protection strikingly as judged by a higher survival, and almost no Aspergillus could be detected in the lung of mice that had received IL-12-transduced HAF-pulsed DCs. These results suggest that antigen-pulsed DCs and IL-12 gene therapy could be used as adjunct therapy for aspergillosis.

Innate Immunity toAspergillusSpecies

“…In contrast, IFN-␥ or IL-12p40 knockout animals (the latter deficient in both IL-12p70 and IL-23) that are treated with cyclophosphamide or neutrophil-depleting antibody are more susceptible to invasive aspergillosis (36,121). Consistent with this, the exogenous administration of IFN-␥ results in improved outcomes of experimental infection for mice treated with corticosteroids or cyclophosphamide (115,155). The cellular source of IFN-␥ in late infection and in immunized mice is recognized as Aspergillus-specific clones of CD4 T cells in both immunocompetent and cyclophosphamide-treated mice (38,135,136), whereas during early infection of neutrophil-depleted mice, the main cellular source of early IFN-␥ is lung NK cells (121).…”

Human Dendritic Cells followingAspergillus fumigatusInfection Express the CCR7 Receptor and a Differential Pattern of Interleukin-12 (IL-12), IL-23, and IL-27 Cytokines, Which Lead to a Th1 Response

“…In these patients a rapid recovery of functional Th1 cells is mandatory in order to control fungal invasion and disease progression. Thus, our results concerning the ability of A. fumigatus to induce a differential pattern of the novel IL-12 family members might be instrumental in reinforcing the new DC-based therapeutic approaches (31,41,45,48). To this end, successful immunization protocols should be …”

Immunosuppressive Effects of CCL17 on Pulmonary Antifungal Responses during Pulmonary Invasive Aspergillosis

“…Most importantly, levels of this cytokine were significantly increased in the CCR4 Ϫ/Ϫ group relative to the CCR4 ϩ/ϩ group at day 2 after conidial challenge. Shao and colleagues (60) recently demonstrated that the transfection of dendritic cells with adenovirus encoding IL-12 and the adoptive transfer of these cells pulsed with heat-inactivated Aspergillus fumigatus protected naive mice from invasive aspergillosis. Further studies will address the relative importance of IL-12 in the innate immune response present in CCR4 Ϫ/Ϫ mice during invasive aspergillosis.…”

“…Inflammatory cytokines such as TNF-␣ (47, 52, 55), IL-12 (54,60), and IL-6 (16) protect, whereas IL-4 (19) predisposes immunocompromised mice to the pulmonary ravages of invasive growth by A. fumigatus. CC chemokines such as CCL2 (through its effects on NK cell recruitment (51) and CCL3 and CXCL1 (through their effects on monocyte/macrophage recruitment) (45, 48) exert prominent protective effects in the context of invasive pulmonary aspergillosis.…”