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Luca Guidotti, D.V.M.

Associate Professor of Experimental Pathology
Department of Immunology and Microbial Science
California Campus
guidotti@scripps.edu
(858) 784-2758

Research Focus

Virus-induced immunopathology

Work from our laboratory is aimed at defining the molecular and cellular bases for liver disease in the pathogenesis of hepatitis B virus (HBV) and other hepatotropic infections. Using HBV transgenic mice and mice infected with adenovirus or lymphocytic choriomeningitis virus (LCMV), we showed that many antigen non-specific inflammatory cells are recruited into the liver by cytotoxic T cells (CTLs) and this process significantly amplifies the severity of liver disease. Recent studies have shown that neutrophils play an important pathogenetic role in our models. Indeed, neutrophils rapidly enter the inflamed organ and recruit most antigen non-specific mononuclear cells via the production of metalloproteinases (i.e. MMP-8 and MMP-9) that facilitate leukocyte trafficking by remodeling of the extracellular matrix. Furthermore, recent results indicated a significant contribution of platelets in the pathogenetic mechanism of CTL-induced liver disease. Platelets accumulate within necroinflammatory foci of the liver and their depletion reduced the intrahepatic number of virus-specific CTLs and significantly ameliorated the severity of liver damage. Since the inhibition of CTL-mediated liver injury can occur under conditions where CTL priming is not involved, it is likely that depletion of platelets impaired the capacity of virus-specific CTLs to migrate into the liver, recognize antigen and/or perform effector functions. In addition, platelets may contribute to immunopathology by directly inducing tissue damage and experiments aimed at defining a direct cytopathic role for platelets are currently underway in our laboratory.

Selected References

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.

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.

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.

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.

Links

Viral Clearance in Acute Hepatitis B Infection