GIAGULLI CINZIA

Pidotimod (PDT) is a synthetic dipeptide with immunomodulatory properties on both innate and adaptive immune response. This research was focused on exploring the possibility to use PDT as an adjuvant molecule able to promote an effective mucosal and systemic immune response, since the antigens administered through mucosal routes are usually weakly immunogenic. The results of this study highlighted the capability of PDT to activate and promote maturation of myeloid dendritic cells of innate immunity and to improve antigen presentation in vivo to the cells of adaptive immunity after intranasal delivery, making this molecule an attractive adjuvant for the development of mucosal vaccine formulations. Then, PDT effects were evaluated on innate immune cells. Recent studies have highlighted in monocytes the PDT capability to antagonize TLR-induced inflammatory response by upregulating the NOD-like receptor Monarch-1/NRLP12, a molecule known to play a crucial role in systemic inflammatory processes. At the moment the studies are focused on identifying possible PDT cell membrane receptor(s) to better understand the mechanism of action of this dipeptide, since it is still unknown despite the numerous studies carried out.

The biological effects of HIV-1 matrix protein p17 and its variants on immune cells and their role in HIV-1 pathogenesis were investigated. First, since all functional activities of p17 are known to depend from its interaction with receptors expressed on immune cells surface (p17Rs), the research was focused on identifying p17Rs and the signal transduction pathways triggered by p17/p17Rs interactions. These studies took to the identification of CXCR1 and CXCR2 as the main p17Rs responsible for the viral protein activities on immune cells. Moreover, this project highlighted the ability of p17 variants, when compared to p17 wild type, of inducing a dysregulation of the PTEN/PI3K/Akt signaling pathway in B cells and to promote B cell growth and clonogenicity, thus suggesting their possible contribution to the development of AIDS-related B cell lymphomas, which still remain a major cause of morbidity and mortality in HIV-1-infected patients. Actually, the research is focused to understand by structure-function studies how mutations in the p17 amino acid sequence are linked to B cell growth and tumorigenesis and by phosphoproteome studies the receptors and signaling cascades responsible of this effect.