Clinical and Research Background
I am trained in clinical medicine, and worked in internal medicine in the UK, including a post as house officer in the Professorial Medical Unit at St Mary’s Hospital. I also spent six months working in general and vascular surgery.
After medicine, I gained a PhD in immunology from University College London, and undertook post-doctoral research work at Scripps Research Institute in La Jolla. As a new Faculty member at Yale, I revealed the function of the liver as a site for the sequestration and destruction of activated T cells (1), the so-called “graveyard model” which has been refined, and modified, but continues to guide contemporary research. This depends upon endotoxin from the intestinal microbiota (2), and regulates systemic immunity (3). This is an important aspect of the biological cross talk between mammals and their microbiome, which is increasingly recognized as essential for immune homeostasis.
Textbooks of immunology assert that initial priming of T cells occurs in lymph nodes, or in the spleen. To challenge this view, we developed and tested the hypothesis that the liver acts as a secondary lymphoid organ. We developed an Adeno-Associated Virus (AAV) model of gene delivery exclusively to hepatocytes, showing that a test antigen expressed in hepatocytes caused local T cell activation (4). In a parallel approach, our lab transplanted a liver from an animal competent to activate CD8+ T cells into a host that could not, and showed that the liver itself had the capacity to fully activate naïve CD8+ T cells (5). Thus, the textbook model does not apply to liver antigens.
Continuing study of the AAV-based gene delivery model showed that hepatocellular antigen directly activates CD8+, but was not cross-presented by bone marrow-derived cells, nor could it activate CD4+ T cells (6). The CD8+ T cell response to such antigens caused immune-inflammatory hepatitis (7), but the local activation of CD8+ T cells alone results in a dysfunctional response that often fails to eliminate the antigen; continuing ineffective immunity is accompanied by liver injury and fibrosis, providing a mouse model of the immunopathogenesis of Hepatitis C (8). We developed a strong interest in the cell biology of antigen presentation by different liver cell types, and devised a novel 3-step approach to their purification, which allows us to directly compare different liver antigen-presenting cells (9). Thus we showed that the capacity to cross-present hepatocyte antigen to CD8+ T cells is widespread in the liver. The distinct immunological functions of different liver cell types led us to devise new ways to target them, using either polyketal nanoparticles (10)or galactosylated low-density lipoproteins as delivery vehicles (11). This approach will be further developed along with selective gene expression and silencing.
We developed a translational research effort though collaboration with a liver transplant surgeon. A living donor liver transplant program allowed us to gain access to healthy human liver leukocytes, obtained by elution from the donor liver vasculature. Using Kupffer cells and liver NK cells, we defined a regulatory circuit in which Kupffer cells respond to different toll-like receptor ligands to activate, or suppress the activation of Kupffer cells (12). We then evaluated the impact of HCV core and NS3 proteins on human Kupffer cell biology, defining immune subversion mechanisms mediated via binding of these proteins to toll-like receptor-2 (13). Ongoing work seeks to define the regulatory circuits controlling gene expression that are thus subverted by HCV.
- Mehal WZ, Azzaroli F, Crispe IN. Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis. J Immunol 2001;167:667-673.
- John B, Crispe IN. TLR-4 regulates CD8+ T cell trapping in the liver. J Immunol 2005;175:1643-1650.
- John B, Klein I, Crispe IN. Immune role of hepatic TLR-4 revealed by orthotopic mouse liver transplantation. Hepatology 2007;45:178-186.
- Wuensch SA, Pierce RH, Crispe IN. Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. J Immunol 2006;177:1689-1697.
- Klein I, Crispe IN. Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med 2006;203:437-447.
- Wuensch SA, Spahn J, Crispe IN. Direct, help-independent priming of CD8+ T cells by adeno-associated virus-transduced hepatocytes. Hepatology 2010;52:1068-1077.
- Giannandrea M, Pierce RH, Crispe IN. Indirect action of tumor necrosis factor-alpha in liver injury during the CD8+ T cell response to an adeno-associated virus vector in mice. Hepatology 2009;49:2010-2020.
- Spahn J, Pierce RH, Crispe IN. Ineffective CD8(+) T-Cell Immunity to Adeno-Associated Virus Can Result in Prolonged Liver Injury and Fibrogenesis. The American journal of pathology 2011;(in press).
- Ebrahimkhani MR, Mohar I, Crispe IN. Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 2011;54:1379-1387.
- Yang SC, Bhide M, Crispe IN, Pierce RH, Murthy N. Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases. Bioconjug Chem 2008;19:1164-1169.
- Wu F, Wuensch SA, Azadniv M, Ebrahimkhani MR, Crispe IN. Galactosylated LDL nanoparticles: a novel targeting delivery system to deliver antigen to macrophages and enhance antigen specific T cell responses. Mol Pharm 2009.
- Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS. TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 2008;205:233-244.
- Tu Z, Pierce RH, Kurtis J, Kuroki Y, Crispe IN, Orloff MS. Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells. Gastroenterology 2010;138:305-314.
Academic and Medical Appointments
Director of MBD Graduate Program, University of Washington, Seattle, WA, 2013-Present
Professor, Department of Pathology, University of Washington, Seattle, WA, 2013-Present
Adjunct Professor, Department of Immunology, University of Washington, Seattle, WA, 2013-Present
Affiliate Professor, Department of Immunology, University of Washington, Seattle, WA, 2009-2013
Member and Professor, Seattle Biomedical Research Institute, Seattle, WA, 2008-Present
Professor of Microbiology and Immunology, University of Rochester, Rochester, NY, 2000-2008
Associate Professor of Immunobiology, Yale Medical School, New Haven, CT, 1994-2000
Assistant Professor of Immunobiology, Yale Medical School, New Haven, CT, 1989-1994
Staff Scientist, NIMR Mill Hill, London, UK, 1987-1989
Senior House Officer, Hammersmith Hospital and Royal Northern, London, UK, 1980-1981
Junior House Officer, St. Mary’s Hospital and Wexham Park, London, UK, 1979-1980
Education and Training
Postdoctoral Fellow, Scripps Research Institute, La Jolla, CA, 1984-1987
University College London, London, UK, Ph.D., 1984
Imperial College of Medicine, London, UK, MB. BS., 1978
University College London, London, UK, B.S., 1975
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