Barbara Bottazzi Principal Investigator View More
- Office Campus, Bldg CVia Rita levi di Montalcino, 2 - 20090 Pieve Emanuele, Milano
The Laboratory of Immunopharmacology is focused on the characterization of soluble factors and cells involved in the innate immune response using in vitro and preclinical models. In addition, the Laboratory is involved in the generation, purification and quality control of recombinant proteins and monoclonal antibodies of interest. Ongoing translational efforts are aimed at validate the use of selected molecules under development as diagnostic and prognostic tools in human pathology.
Biochemical and biological characterization of the long pentraxin 3 (PTX3)
A first interest of the Laboratory is represented by the long pentraxin PTX3, a multifunctional molecule produced by stromal and immune cells involved in the response to selected pathogens. Since the original cloning of the protein, the Laboratory has been working on the biochemical and structural characterization of PTX3. Ongoing efforts are aimed at i) define the structural characteristics of PTX3; ii) investigate the biological role of PTX3, in particular its interplay with the Complement system; iii) validate the use of PTX3 as diagnostic and prognostic marker in human pathology.
The long pentraxin PTX3 was identified in the late 80’s as a gene rapidly induced in endothelial cells and macrophages by proinflammatory stimuli (IL-1 and TNF) and LPS. The protein is a member of the pentraxin family: prototypes of this family are C reactive protein (CRP) and Serum amyloid P component (SAP) two well-known acute phase proteins in man and mouse respectively. Data obtained so far indicate that PTX3 is induced by different stimuli in myeloid and stromal cells. PTX3 is an elongated multimeric protein made by eight identical protomers stabilized by dysulphide bonds. Each protomer is characterized by a C-terminal pentraxin like domain associated to a long N-terminal domain unrelated to other known protein. PTX3 is a multifunctional molecule at the crossroad of innate immunity, inflammation, matrix remodeling and fertility. In particular, it has been described that PTX3 can regulate Complement activity through the interaction with different components of the three Complement cascades. In addition, PTX3 participates in remodeling after wound healing, exerts non-redundant protective activities against selected microbes and acts as oncosuppressive gene. Available data suggest that PTX3 can be a biomarker of human pathology, in particular in the context of cardiovascular diseases and infections. Presently the laboratory is involved in the structural characterization of PTX3 and in defining the structural requirements essential for the biological activity, focusing in particular on the interplay with the Complement system. In addition, we are addressing the role of PTX3 in infections in the context of the lymphatic system using preclinical models. Finally, efforts are ongoing to further support the role of PTX3 as novel biomarker in collaboration with different clinical partners.
Novel markers of macrophage polarization
A second field of interest concern the characterization of novel molecules associated to macrophage polarization, in particular, we are focused on two molecules expressed by M2 polarized macrophages: a soluble molecule called migration stimulating factor (MSF) and a membrane protein belonging to the tetraspanin family, called Membrane Spanning 4-Domains A4A (MS4A4A). Tumor associate macrophages are M2-like cells infiltrating tumors and. Data collected so far indicate that TAM contribute to the neoplastic progression rather than contrasting tumor growth.
Macrophages are a key component of the tumor microenvironment. Increasing evidences indicate that tumor associated macrophages (TAM) can promote tumor growth and are associated to poor prognosis. TAM are characterized by a M2-like phenotype that can explain the tumor-promoting properties and the suppression of adaptive immune responses. TAM have thus emerged as key determinants of response to current immunotherapies and as prognostic indicators and therapeutic targets. In this context, the development of molecules selectively expressed by M2-like TAM provide possible novel antineoplastic tools.
Membrane Spanning 4-Domains A4A
MS4A4A is a tetraspanin molecule exclusively expressed in M2 polarized macrophages. MS4A4A belongs to the same tetraspanin family as CD20, a validated clinical therapeutic target. We are developing monoclonal antibodies targeting the molecule expressed by macrophages. In addition, we are using preclinical models of carcinogenesis and tumor growth in gene modified animals to characterize the biological properties of the molecule.
Migration Stimulating Factor
MSF is a truncated isoform of human fibronectin 1 (FN1), identical to FN1 N-terminal portion, but containing a unique series of 10 aminoacids in the C-terminal end. MSF was found to be selectively expressed by M2 and M2-like macrophages, including TAM. MSF is a potent inducer of migration of monocytes and selected tumor cells. We have generated mAb and MSF ELISA. Current work has the aim to investigate the spectrum and mechanism of action of MSF in tumor invasion, its motogenic properties for cells of the monocyte-macrophage lineage and its value as biomarker of neoplastic transformation.
Barbara Bottazzi Publications
Selected Publications: 20-25 publications listed in details with all the contributing authors, title of the papers, journal, dates. 1: Mattiola I, Tomay F, De Pizzol M, Silva-Gomes R, Savino ...