Ian Nicholas Crispe, M.B. B.S., Ph.D.
Affiliate Professor of Immunology

Seattle Biomedical Research Institute
307 North Westlake Ave.
Seattle WA 98109.
Tel: 206-256-7163
Fax: 206-256-7229
nick.crispe@sbri.org

Crispe Lab at SBRI

Dr Crispe is a Full Member of the Malaria Program at the Seattle Biomedical Research Inssitute, an Affiliate Professor of Immunology, and a member of the Pathobiology Graduate
Program at the University of Washington. Previously he was Professor of Microbiology and Immunology, Professor of Medicine, and the Associate Director of the David H Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center. 

Dr. Crispe trained in Medicine at St Mary’s Medical School in London, England (now Imperial College of Medicine), and worked as a clinician at St Mary’s and at the Postgraduate Medical School, Hammersmith before graduate work at University College London, resulting in a Ph.D. His post-doctoral work in developmental immunology in the laboratory of Dr Michael Bevan, FRS, produced the first lineage map of precursor thymocytes, before interest moved to the lymphoid periphery and the liver. He has participated in NIH peer-review, written reviews in both developmental and liver immunology, and was the 2006 Hans Popper Distinguished Basic Science Lecturer of the American Association for the Study of Liver Disease.

Crispe Lab Research Program

The central research mission of the lab is to understand the distinctive features of immune responses that are generated in the liver, and reveal aspects of T cell function that are prominent in this environment. We are driven by the central idea that liver antigens can prime T cells locally, and that such priming has distinctive requirements in terms of the cell types competent to act as APC, the need for CD4+ T cell help in CD8+ T cell responses, the involvement of the innate immune system, and the long-term fate of such liver-primed T cells. This research agenda has led us to build expertise in Kupffer cell biology, and we view these cells as central in determining whether immune responses are biased towards immunity or tolerance.

Multiple important pathogens target the liver, including viral hepatitides and malaria. Therefore, we are interested in the immune responses to such pathogens, and seek to model some aspects of their immunopathology in vitro. We have developed an Adeno-Associated Virus (AAV)-based model for gene delivery to hepatocytes, and find that the CD8+ T cell response to this vector may be used to study T cell-dependent hepatitis, liver injury and fibrogenesis. Thus, we are dissecting the role of T cell- and Kupffer cell-derived cytokines in the development of liver immunopathology. Since AAV is a strong candidate vector for gene therapy, our investigations are relevant to efforts to improve this type of therapy, and in particular to negate the immune response to AAV vectors.

The lab has recently developed an experimental program related to the liver stage of malaria. The malaria parasite interacts with liver endothelial cells, Kupffer cells and hepatocytes during its development, and we are studying these interactions to look for evidence of immune subversion. The development of genetically-modified parasites that act as live vaccines has made it possible to study the mechanism of immune protection against malaria in mice. We use his model to study T cell priming to liver-stage antigens and the mechanisms of effective immunity against the infected hepatocyte.

Selected Publications

Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases.  Yang SC, Bhide M, Crispe IN, Pierce RH, Murthy N. Bioconjug Chem. 2008 Jun;19(6):1164-9. Epub 2008 May 24.  PMID: 18500834

E2F4 modulates differentiation and gene expression in hematopoietic progenitor cells during commitment to the lymphoid lineage.  Enos ME, Bancos SA, Bushnell T, Crispe IN.  J Immunol. 2008 Mar 15;180(6):3699-707.  PMID: 18322175

TLR-dependent cross talk between human Kupffer cells and NK cells.  Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS.  J Exp Med. 2008 Jan 21;205(1):233-44. Epub 2008 Jan 14.  PMID: 18195076

Imaging CD8+ T cell dynamics in vivo using a transgenic luciferase reporter.  Azadniv M, Dugger K, Bowers WJ, Weaver C, Crispe IN.  Int Immunol. 2007 Oct;19(10):1165-73. Epub 2007 Aug 14.  PMID: 17698980

Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages.  Klein I, Cornejo JC, Polakos NK, John B, Wuensch SA, Topham DJ, Pierce RH, Crispe IN.  Blood. 2007 Dec 1;110(12):4077-85. Epub 2007 Aug 9.  PMID: 17690256

Early intrahepatic accumulation of CD8+ T cells provides a source of effectors for nonhepatic immune responses.  Polakos NK, Klein I, Richter MV, Zaiss DM, Giannandrea M, Crispe IN, Topham DJ.  J Immunol. 2007 Jul 1;179(1):201-10.  PMID: 17579039

The activation state of human intrahepatic lymphocytes.  Tu Z, Bozorgzadeh A, Crispe IN, Orloff MS.  Clin Exp Immunol. 2007 Jul;149(1):186-93. Epub 2007 May 18.  PMID: 17511774

A microsurgical approach to hepatic and extrahepatic antigen presentation and its effects on the migration pattern of activated CD8(+) T cells.  Klein I, Gassel HJ, Thiede A, Crispe IN, Steger U.  Microsurgery. 2007;27(4):289-94.  PMID: 17477402

Immune role of hepatic TLR-4 revealed by orthotopic mouse liver transplantation.  John B, Klein I, Crispe IN.  Hepatology. 2007 Jan;45(1):178-86.  PMID: 17187407

Cytotoxic T-cell response following mouse liver transplantation is independent of the initial site of T-cell priming.  Klein I, Gassel HJ, Crispe IN.  Transplant Proc. 2006 Dec;38(10):3241-3.  PMID: 17175235

Cellular and molecular mechanisms of liver tolerance.  Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S.  Immunol Rev. 2006 Oct;213:101-18. Review.  PMID: 16972899

Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation.  Wuensch SA, Pierce RH, Crispe IN.  J Immunol. 2006 Aug 1;177(3):1689-97.  PMID: 16849478

Kupffer cell-dependent hepatitis occurs during influenza infection.  Polakos NK, Cornejo JC, Murray DA, Wright KO, Treanor JJ, Crispe IN, Topham DJ, Pierce RH.  Am J Pathol. 2006 Apr;168(4):1169-78; quiz 1404-5.   PMID: 16565492

Complete differentiation of CD8+ T cells activated locally within the transplanted liver.  Klein I, Crispe IN.  J Exp Med. 2006 Feb 20;203(2):437-47. Epub 2006 Feb 13.  PMID: 16476766

Expression of hepatitis C virus core protein in hepatocytes does not modulate proliferation or apoptosis of CD8+ T cells.  Jin YH, Crispe IN, Park S.  Yonsei Med J. 2005 Dec 31;46(6):827-34.  PMID: 16385660

TLR-4 regulates CD8+ T cell trapping in the liver.  John B, Crispe IN.  J Immunol. 2005 Aug 1;175(3):1643-50. PMID: 16034104

Quantitative PCR for detection of the OT-1 transgene.  Wright KO, Murray DA, Crispe NI, Pierce RH.  BMC Immunol. 2005 Aug 24;6:20.  PMID: 16120215

TNF-alpha controls intrahepatic T cell apoptosis and peripheral T cell numbers.  Murray DA, Crispe IN.  J Immunol. 2004 Aug 15;173(4):2402-9.  PMID: 15294953

The E2F-1 transcription factor promotes caspase-8 and bid expression, and enhances Fas signaling in T cells.  Cao Q, Xia Y, Azadniv M, Crispe IN.  J Immunol. 2004 Jul 15;173(2):1111-7.  PMID: 15240700

Passive and active mechanisms trap activated CD8+ T cells in the liver.  John B, Crispe IN.  J Immunol. 2004 May 1;172(9):5222-9.  PMID: 15100260

Overexpression of IL-7R alpha provides a competitive advantage during early T-cell development.  Laouar Y, Crispe IN, Flavell RA.   Blood. 2004 Mar 15;103(6):1985-94. Epub 2003 Oct 30.  PMID: 14592827

Contrasting urban and rural lifestyles of memory CD8+ T cells.  Topham DJ, Crispe IN.  Immunity. 2003 May;18(5):584-6. PMID: 12753734

P27kip1 regulates the cell cycle arrest and survival of activated T lymphocytes in response to interleukin-2 withdrawal.  Huleatt JW, Cresswell J, Bottomly K, Crispe IN.  Immunology. 2003 Apr;108(4):493-501.  PMID: 12667211

Hepatic T cells and liver tolerance.  Crispe IN.  Nat Rev Immunol. 2003 Jan;3(1):51-62. Review.  PMID: 12511875

Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization.  Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle PA, Hamann A, Crispe IN.  J Immunol. 2002 Sep 1;169(5):2407-13.  PMID: 12193708

Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes.  Azzaroli F, Mehal W, Soroka CJ, Wang L, Lee J, Crispe N, Boyer JL.  Hepatology. 2002 Jul;36(1):49-54.  PMID: 12085348

Biology and significance of T-cell apoptosis in the liver. Park S, Murray D, John B, Crispe IN.  Immunol Cell Biol. 2002 Feb;80(1):74-83. Review.  PMID: 11869364

Cleavage of E2F-1-regulating proteins and activation of E2F-1 during CD95-induced death of thymocytes.  Bi B, Littlewood NK, Crispe IN.  Immunology. 2001 Sep;104(1):37-42.  PMID: 11576218

Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis.  Mehal WZ, Azzaroli F, Crispe IN.  J Immunol. 2001 Jul 15;167(2):667-73.  PMID: 11441069

Isolation of mouse intrahepatic lymphocytes.  Crispe IN.  Curr Protoc Immunol. 2001 May;Chapter 3:Unit 3.21. PMID: 18432786

Specific blockade by CD54 and MHC II of CD40-mediated signaling for B cell proliferation and survival.  Doyle IS, Hollmann CA, Crispe IN, Owens T.  Exp Cell Res. 2001 May 1;265(2):312-8.  PMID: 11302697

Immunology of the healthy liver: old questions and new insights.  Mehal WZ, Azzaroli F, Crispe IN.  Gastroenterology. 2001 Jan;120(1):250-60. Review. No abstract available. PMID: 11208734

Involvement of CD1 in peripheral deletion of T lymphocytes is independent of NK T cells.  Dao T, Exley M, Mehal WZ, Tahir SM, Snapper S, Taniguchi M, Balk SP, Crispe IN.  J Immunol. 2001 Mar 1;166(5):3090-7.  PMID: 11207260

CD95/Fas signaling in T lymphocytes induces the cell cycle control protein p21cip-1/WAF-1, which promotes apoptosis.  Hingorani R, Bi B, Dao T, Bae Y, Matsuzawa A, Crispe IN.  J Immunol. 2000 Apr 15;164(8):4032-6.  PMID: 10754295

Differential regulation of cell cycle-related proteins by CD95 engagement in thymocytes and T cell leukemic cell line, Jurkat.  Bae Y, Crispe IN.  J Cell Biochem. 2001;80(3):328-38.  PMID: 11135362

Functional flexibility in T cells: independent regulation of CD4+ T cell proliferation and effector function in vivo.  Laouar Y, Crispe IN.  Immunity. 2000 Sep;13(3):291-301.  PMID: 11021527

Induction of murine hepatocyte death by membrane-bound CD95 (Fas/APO-1)-ligand: characterization of an in vitro system.  Schlosser SF, Azzaroli F, Dao T, Hingorani R, Nicholas Crispe I, Boyer JL.  Hepatology. 2000 Oct;32(4 Pt 1):779-85.  PMID: 11003622

The liver as a site of T-cell apoptosis: graveyard, or killing field?  Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP.  Immunol Rev. 2000 Apr;174:47-62. Review.  PMID: 10807506

Do natural T cells promote liver regeneration?  Crispe IN.  Hepatology. 2000 Apr;31(4):1022-4. Review. PMID: 10733562

Prometheus through the looking glass: reflections on the hepatic immune system.  O'Farrelly C, Crispe IN.  Immunol Today. 1999 Sep;20(9):394-8. No abstract available. PMID: 10532788

Death and destruction of activated T lymphocytes.  Crispe IN.  Immunol Res. 1999;19(2-3):143-57. Review. PMID: 10493169

Selective retention of activated CD8+ T cells by the normal liver.  Mehal WZ, Juedes AE, Crispe IN. J Immunol. 1999 Sep 15;163(6):3202-10.  PMID: 10477588

Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo.  Zheng TS, Schlosser SF, Dao T, Hingorani R, Crispe IN, Boyer JL, Flavell RA.  Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13618-23. PMID: 9811849

Posted 9/15/09