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Immunology and Microbial Science

Luca Guidotti, D.V.M.

Associate Professor Adjunct
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

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Faculty

Andersen, Kristian G.
Baccala, Roberto
Burton, Dennis
Chisari, Frank
Choe, Hyeryun
Cochrane, Charles
Dai, Yang D
de la Torre, Juan C.
DerMardirossian, Celine
Edgington, Thomas S.
Elder, John
Farzan, Michael
Feeney, Ann
Franc, Nathalie
Gallay, Philippe
Garaigorta De Dios, Urtzi
Gavin, Amanda
Hangartner, Lars
Havran, Wendy
Kang, Young Jun
Kim, Dae Hee
Kirak, Oktay
Kono, Dwight
Kravchenko, Vladimir
Lasmezas, Corinne
Law, Mansun
Lawson, Brian
McHeyzer-Williams, Michael
Mosier, Donald
Nemazee, David
Nemerow, Glen
Oldstone, Michael B.A.
Petrie, Howard
Reisfeld, Ralph
Ruf, Wolfram
Saphire, Andrew
Saphire, Erica Ollmann
Sauer, Karsten
Schief, William
Sherman, Linda
Song, Byeong Doo
Sullivan, Brian
Teijaro, John
Tellinghuisen, Timothy
Teyton, Luc
Theofilopoulos, Argyrios
Ulevitch, Richard
Valente, Susana Tereno
Weissmann, Charles
Whitton, J. Lindsay
Wyatt, Richard
Xiao, Changchun
Zhu, Jiang
Zwick, Michael

Affiliated Faculty

Getzoff, Elizabeth
Janda, Kim
Kaufmann, Gunnar Joerg F
Paulson, James C.
Torbett, Bruce

Adjunct Faculty

Dennis, Edward
Ditzel, Henrik
Feuer, Ralph
Gascoigne, Nicholas
Ghazal, Peter
Guidotti, Luca
Han, Jiahuai
Isogawa, Masanori
Knaus, Ulla
Mackman, Nigel
Jameson, Julie
McGavern, Dorian
McKay, Dianne
Merson, James
Poignard, Pascal
Sette, Allessandro
Sigurdson, Christina
Sprent, Jonathan
Surh, Charles