Luca Guidotti
Luca Guidotti
e-mail:
affiliation: San Raffaele Scientific Institute
research area(s): Immunity And Infection, Experimental Medicine
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
Training:

Biochemistry: Fellow, Institute of Biochemistry, Medical School, University of Milan, Milan, Italy, 1986-1989.

Pathology: Fellow, Institute of Pathology, Medical School, University of Parma, Parma, Italy, 1990-1991.

Experimental Pathology: Fellow, Division of Experimental Pathology, The Scripps Research Institute, 1992-1994.


Employment:

1992-1995 Assistant Professor, Institute of General Pathology, University of Parma Medical School, Parma, Italy.

1995-1999 Assistant Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

1999-present Associate Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.

2004-present Head, Immunopathology Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy.

2008-present Director, Diabetes Research Institute (DRI), DIBIT, San Raffaele Scientific Institute, Milan, Italy.

2011-present Adjunct Professor, Department of Immunology, Sanford-Burnham Medical Research, La Jolla, CA, USA.


Professional Activities:

Reviewer for Nature, Nature Medicine, Science, PNAS, The Lancet, J. Exp. Med., Journal of Clinical Investigation, PloS Pathogens, Am. J. Pathol., J. Immunol., J. of Virol., Virol., J. Infectious Diseases, Human Gene Therapy, Hepatology, Journal of Hepatology.

Reviewer, NIH General Medicine(GM) 2, Study Section, 1998-1999.
Reviewer, NIH Virology (VR), Study Section, 2000-2001.
Reviewer, Special Study Section (ZRG MBC-2), November 2001.
Reviewer, RFP-NIH-NIAID-DAIDS 02-19 "Drug Development for Opportunistic Infections: Hepatitis C" Study Section ZAI1-GPJ-A-C1, February 2002.
Reviewer for The Wellcome Trust, UK, Project Grants, 2002-2003.
Reviewer for the European Research Council (ERC-2007-StG, Ideas Specific Programme), 2007 and 2010.
Reviewer, RFA-ZDK1-GRB-G "Hepatitis B Clinical Research Network" Review, July 2008.
Reviewer, BMRC & NMRC Singapore Grants, 2008-2010.
Reviewer, Recovery act limited competition: NIH directors opportunity for research in five thematic areas (RC4, May 2010)


Professional Societies:

Henry Kunkel Society, American Association of Immunology, American Society for Microbiology.


Memberships, Committees and Prizes:

1995-present: Recipient, NIH/NIAID RO1 grant AI040696: "Regulation of HBV Replication by the Immune System".
1998-present: Member, Organizing Committee, NIH/NIAID-sponsored Annual International Meeting on Hepatitis Viruses.
2001: Gold Medal for excellence in Antiviral Research, Schering Plough Japan, Tokyo, Japan.
2003: Member, NIH/NIAID Advisory Panel for the Study of Liver Diseases.
2004: Honorary Member, Academic Society of Philosophy and Medicine, University of Parma, Italy.
2008: Charter Member, Eureka Institute for Translational Medicine, (http://www.eurekainstitute.org).
2009: Member, University California San Diego (UCSD), Center for AIDS Research (CFAR).
2010: Recipient, European Research Council (ERC) Advanced Grant 250219: "Imaging liver immunopathology by intravital microscopy (IVM): a new approach to study the pathogenesis of hepatitis B virus (HBV) infection".
Our research program aims at dissecting the cellular and molecular mechanisms responsible for immunopathological responses, with particular emphasis on the responses that occur during infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HBV and HCV are noncytopathic viruses causing acute and chronic hepatitis of variable duration and severity. Over 700 million people worldwide are chronically infected by these viruses and about 2 million of them die each year from complications (e.g. cirrhosis and hepatocellular carcinoma, HCC) of these infections. Our program takes advantage of infected patients, proprietary mouse models of infection and new technological advances in the field of live imaging (e.g. intravital microscopy). Using these resources we plan to tackle a number of unresolved issues that comprise the means by which virus-specific T cells traffic and recognize viral antigens within the normal, cirrhotic or cancerous livers and the cellular/molecular basis for disease resolution. Pertinent to the latter we have recently demonstrated that Kupffer cells, the intravascular liver-resident macrophages, limit the severity of immunopathology during viral hepatitis by removing apoptotic hepatocytes in a scavenger receptor-dependent manner. Having also recently described a novel role for platelets in the pathogenesis of viral hepatitis (i.e. platelets adhering to activated endothelium of the liver microcirculation become activated and promote the influx of pathogenic virus-specific T cells into the organ parenchyma), we are performing a large preclinical trial evaluating the impact of anti-platelet therapy on the severity of immune-mediated chronic liver injury and the development of HCC. Additional preclinical activities of our laboratory include the implementation of novel strategies attempting to cure established HCC, such as the local delivery of anticancer drugs through cell-based approaches that involve the manipulation of tumor-infiltrating monocytes.
1. Guidotti, L.G. and F.V. Chisari. Noncytolytic control of viral infections by the innate and adaptive immune response. Review. Annu. Rev. Immunol. 19:65-91, 2001.

2. Kakimi, K., T. E. Lane, S. F. Wieland, V.C. Asensio, I. L. Campbell, F.V. Chisari and L.G. Guidotti. Blocking chemokine responsive to {gamma}"2/interferon (IFN)-{gamma} inducible protein and monokine induced by IFN-{gamma} activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus"specific cytotoxic T lymphocytes J. Exp. Med. 194:1755-1766, 2001.

3. Sitia G., M. Isogawa, K. Kakimi, S.F. Wieland, F.V. Chisari and L.G. Guidotti. Depletion of neutrophils blocks the recruitment of antigen non-specific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes. Proc. Nat'l Acad. Sci, USA 99:13717-13722, 2002.

4. Sitia G., M. Isogawa, M. Iannacone, I.L. Campbell, F.V. Chisari and L.G. Guidotti. MMPs are required for recruitment of antigen non-specific mononuclear cells into the liver by CTLs. J. Clinical Investigation. 113:1158-1167, 2004.

5. Iannacone, M., G. Sitia G., M. Isogawa, P. Marchese, M.G. Castro, P.R. Lowenstein, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat. Med. 11:1167-1169, 2005.

6. Guidotti, L.G. and F.V. Chisari. Immunobiology and pathogenesis of viral hepatitis. Review. Annu. Rev. Pathology. 1:23-61, 2006.

7. Iannacone, M., G. Sitia, M. Isogawa, J.K. Whitmire, P. Marchese, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets prevent IFN-a/b-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc. Nat'l Acad. Sci, USA 105:629-634, 2008.

8. De Palma M., R. Mazzieri, L.S. Politi, F. Pucci, E. Zonari, G. Sitia, S. Mazzoleni, D. Moi, M.A. Venneri, S. Indraccolo, A. Falini, L.G. Guidotti, R. Galli and L. Naldini. Tumor-targeted interferon-α delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell, 14:299-311, 2008.

9. Iannacone, M., E.A. Moseman, E. Tonti, L. Bosurgi, T. Junt, S.E. Henrickson, S.P. Whelan, L.G. Guidotti and U.H. von Andrian. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465:1079-83, 2010.

10. Sitia G., M. Iannacone, R. Aiolfi, M. Isogawa, N. van Rooijen, C. Scozzesi, M.E. Bianchi, U.H. von Andrian, F.V. Chisari and L.G. Guidotti. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. Plos Pathogens, Jun;7(6):e1002061. Epub 2011 Jun 2.
Project Title:
IMAGING LIVER IMMUNOPATHOLOGY BY INTRAVITAL MICROSCOPY
Objective. The objective of this program is to take advantage of technological progresses in the field of live imaging recently developed in our laboratory to elucidate the pathogenesis of hepatitis B virus (HBV) infection.

Background/Rationale. Cytotoxic T lymphocytes (CTL) play a major part in the development of liver disease and the resolution of HBV infection. A number of important issues pertaining to HBV pathogenesis remain unresolved and they include the way in which CTL traffic and recognize antigen within the liver and the way in which the diseased liver influences these processes. Our rationale is based on the notion that - at last - we can address these and other related issues experimentally.

Description of the project. Single- and two-photon intravital microscopy will be carried out in un-inflamed, fibrotic/cirrhotic or cancerous livers from mouse models that include transgenic mice that express all of the viral polypeptides and replicate HBV in the hepatocyte and normal mice infected with HBV-replicating, hepatotropic, fluorescent adenoviruses. The spatial and temporal constraints of naïve or effector HBV-specific CTL recognizing viral antigens and interacting intrahepatically with platelets, endothelial cells or Kupffer cells will be visualized thanks to experimental systems created specifically for this purpose.

Anticipated output. These studies will shed new light on previously unknown aspects of HBV pathogenesis, paving the road to new immunotherapeutic strategies aimed at terminating chronic HBV infection.

Key references
1. Iannacone, M., G. Sitia G., M. Isogawa, P. Marchese, M.G. Castro, P.R. Lowenstein, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat. Med. 11:1167-1169, 2005.
2. Iannacone, M., G. Sitia, M. Isogawa, J.K. Whitmire, P. Marchese, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets prevent IFN-a/b-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc. Nat'l Acad. Sci, USA 105:629-634, 2008.
3. Iannacone, M., E.A. Moseman, E. Tonti, L. Bosurgi, T. Junt, S.E. Henrickson, S.P. Whelan, L.G. Guidotti and U.H. von Andrian. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465:1079-83, 2010.
4. Sitia G., M. Iannacone, R. Aiolfi, M. Isogawa, N. van Rooijen, C. Scozzesi, M.E. Bianchi, U.H. von Andrian, F.V. Chisari and L.G. Guidotti. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. Plos Pathogens, Jun;7(6):e1002061. Epub 2011 Jun 2.


Project Title:
A NOVEL APPROACH FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA
Objective. The objective of this project is to use mouse models of chronic HBV infection to test safety and efficacy of novel anti-platelet therapies aimed at preventing/delaying the onset of hepatocellular carcinoma (HCC).

Background/Rationale. We have recently used mouse models of acute hepatitis B virus (HBV) infection to show that platelets play a crucial and previously unrecognized role in liver disease pathogenesis. Indeed, upon activation, platelets contribute to liver injury by promoting the recruitment of virus-specific cytotoxic T lymphocytes (CTL) into the liver parenchyma. We also showed that a dysfunctional and detrimental virus-specific CTL response is responsible of HCC development in mouse models of chronic HBV infection.

Description of the project. Experimentally, the project will involve state-of-the-art techniques pertaining to i) immunomonitoring (such as FACS analyses of CTL responses in blood, spleen, liver), ii) platelet responses (such as FACS analyses of platelet markers and ex-vivo aggregation tests of platelet function) and liver pathology (from histological and immunohistochemical approaches ex-vivo to non-invasive magnetic resonance imaging (MRI)-based HCC analyses in live animals).

Anticipated output. We believe that findings emerging from these preclinical studies may set an important proof of principle for anti-platelet treatment of chronic HBV and HCC in humans.

Key references
1. Iannacone, M., G. Sitia G., M. Isogawa, P. Marchese, M.G. Castro, P.R. Lowenstein, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat. Med. 11:1167-1169, 2005.
2. Iannacone, M., G. Sitia, M. Isogawa, J.K. Whitmire, P. Marchese, F.V. Chisari, Z.M. Ruggeri and L.G. Guidotti. Platelets prevent IFN-a/b-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc. Nat'l Acad. Sci, USA 105:629-634, 2008.
3. Iannacone, M., E.A. Moseman, E. Tonti, L. Bosurgi, T. Junt, S.E. Henrickson, S.P. Whelan, L.G. Guidotti and U.H. von Andrian. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465:1079-83, 2010.
Sitia G., M. Iannacone, R. Aiolfi, M. Isogawa, N. van Rooijen, C. Scozzesi, M.E. Bianchi, U.H. von Andrian, F.V. Chisari and L.G. Guidotti. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. Plos Pathogens, Jun;7(6):e1002061. Epub 2011 Jun 2.