Tiziana Di Pucchio

Type I IFN as a Natural Adjuvant for a Protective Immune Response: Lessons from the Influenza Vaccine Model

The identification of natural adjuvants capable of selectively promoting an efficient immune response against infectious agents would represent an important advance in immunology, with direct implications for vaccine development, whose progress is generally hampered by the difficulties in defining powerful synthetic adjuvants suitable for clinical use. Here, we demonstrate that endogenous type I IFN is necessary for the Th1 type of immune response induced by typical adjuvants in mice and that IFN itself is an unexpectedly powerful adjuvant when administered with the human influenza vaccine, for inducing IgG2a and IgA production and conferring protection from virus challenge. The finding that these cytokines, currently used in patients, are necessary for full expression of adjuvant activity and are sufficient for the generation of a protective immune response opens new perspectives in understanding the basis of immunity and in vaccine development.

Potent Immune Response against HIV-1 and Protection from Virus Challenge in hu-PBL-SCID Mice Immunized with Inactivated Virus-pulsed Dendritic Cells Generated in the Presence of IFN-α

A major challenge of AIDS research is the development of therapeutic vaccine strategies capable of inducing the humoral and cellular arms of the immune responses against HIV-1. In this work, we evaluated the capability of DCs pulsed with aldrithiol-2–inactivated HIV-1 in inducing a protective antiviral human immune response in SCID mice reconstituted with human PBL (hu-PBL-SCID mice). Immunization of hu-PBL-SCID mice with DCs generated after exposure of monocytes to GM-CSF/IFN-α (IFN-DCs) and pulsed with inactivated HIV-1 resulted in a marked induction of human anti–HIV-1 antibodies, which was associated with the detection of anti-HIV neutralizing activity in the serum. This vaccination schedule also promoted the generation of a human CD8+ T cell response against HIV-1, as measured by IFN-γ Elispot analysis. Notably, when the hu-PBL-SCID mice immunized with antigen-pulsed IFN-DCs were infected with HIV-1, inhibition of virus infection was observed as compared with control animals. These results suggest that IFN-DCs pulsed with inactivated HIV-1 can represent a valuable approach of immune intervention in HIV-1–infected patients.

The natural alliance between type I interferon and dendritic cells and its role in linking innate and adaptive immunity.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and thus play a pivotal role in induction of the immune response. Recent studies in both human and mouse models have shown that type I IFN, cytokines originally characterized for their antiviral activity and exerting multiple biologic effects, efficiently promote the differentiation and activation of DCs. These observations, together with the findings that DCs can express biologically relevant levels of type I interferon (IFN) and, in particular, that high amounts of these cytokines are released by specialized DC precursors (i.e., plasmacytoid DCs) in response to viral infections, strongly suggest the existence of a natural alliance between type I IFN and DCs, which is instrumental in ensuring an efficient immune response to both infectious agents and tumors. Further recent knowledge on the interactions between type I IFN and DCs emphasizes the importance of these cytokines in linking innate and adaptive immunity and may lead to new perspectives in their use as vaccine adjuvants as well as in strategies for the development of DC-based vaccines.

Inhibitors of indoleamine 2,3-dioxygenase: a review of novel patented lead compounds

Importance of the field: The enzyme indoleamine 2,3-dioxygenase (IDO) regulates immune responses through the capacity to degrade the essential amino-acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favour the differentiation of regulatory T cells. The current experimental evidence indicates that IDO can be expressed by a variety of cell types, including dendritic cells, tumour cells and stromal cells. Recently, IDO has been implicated in B-cell stimulation and autoantibody production in experimental models of autoimmune diseases. Areas covered in this review: Advances in the biochemistry of IDO and our understanding of the biological relevance of IDO-mediated tryptophan consumption to the establishment of immune tolerance are summarised and discussed. A selection of recent patents in the field are also reviewed and analysed. What the reader will gain: Readers will gain an overview of the patented compounds with IDO inhibitory activity from an immunologists perspective. They will also learn about the companies that are main players in the field. Take home message: Current evidence points to IDO as a molecular target for therapeutic intervention in order to restrain unwanted inflammatory/autoimmune responses and/or to boost antitumour immunity.

CD2+/CD14+ monocytes rapidly differentiate into CD83+ dendritic cells

Since denditric cells (DC) represent the main players linking innate and adaptive immunity, their prompt generation from blood cells would be instrumental for an efficient immune response to infections. Consistent with this, CD2+ monocytes were found to express the DC maturation marker CD83, along with acquisition of high antigen‐presenting activity, after a surprisingly short time in culture. This rapid process is associated with expression of IFN‐α/β genes and secretion of low levels of pro‐inflammatory cytokines. Exposure of monocytes to IFN‐α, but not to IL‐4, induced persistence of CD2+/CD83+ cells, which were fully competent in stimulating primary responses by naive T cells. These results unravel the natural pathway by which infection‐induced signals rapidly transform pre‐armed monocytes into active DC.