application) The candidate has three years post-doctoral research experience, and will be shortly be completing his subspecialty training in hepatology and gastroenterology. This application for the mentored K08 award is submitted with the goal of providing the candidate with the further experience and training necessary to function as an independent investigator working in the field of liver immunology. The project's long-term objectives are to understand the mechanisms which result in sub-optimal T cell responses in the liver. This is a prerequisite for developing strategies to enhance the immune response against chronic infections of the liver including viral hepatitis B and C. We and others have demonstrated that in-vivo CD8+ T cell activation induced T cell death results in liver accumulation and apoptosis of CD8+ T cells. This lead to the hypothesis that the liver is a specific site for the removal of activated CD8+ T cells. The preliminary data demonstrates that activated CD8+ T cells flowing through the normal liver are retained by an ICAM-1 dependent mechanism (hepatic retention). The retained cells are in contact with liver macrophages (Kupffer cells), and a proportion undergo apoptosis after 14 hours of hepatic retention. The candidate proposes to; 1) Establish the proportion of activated CD8+ T cells that are undergoing apoptosis in the liver. II) Test the requirement for Kupffer cells during hepatic retention of CD8+ T cells. III) Determine if specific peptide in the liver results in division and apoptosis of activated CD8+ T cell. IV) Determine if intra-hepatic presentation of hepatocyte antigens by bone marrow derived cells results in CD8+ T cell priming or apoptosis. The Section of Immunobiology at Yale University is ideal for training because of the quality of the faculty, the breadth of their research, their experience as mentors and the core facilities at Yale. The School of Medicine has pledged protected time for the candidate during this training period prior to functioning as an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK002965-01
Application #
6233012
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$126,900
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Watanabe, Azuma; Hashmi, Ardeshir; Gomes, Dawidson Assis et al. (2007) Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46:1509-18
Hashmi, Ardeshir Z; Hakim, Wyel; Kruglov, Emma A et al. (2007) Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 292:G395-401
Qamar, Amir; Sheikh, Shehzad Zafar; Masud, Ali et al. (2006) In vitro and in vivo protection of stellate cells from apoptosis by leptin. Dig Dis Sci 51:1697-705
Kim, Sangwon V; Mehal, Wajahat Z; Dong, Xuemei et al. (2006) Modulation of cell adhesion and motility in the immune system by Myo1f. Science 314:136-9
Kuniyasu, Yuhshi; Qamar, Amir; Sheikh, Shehzad Zafar et al. (2005) Blocking intrahepatic deletion of activated CD8+ T cells by an altered peptide ligand. Cell Immunol 238:31-7
Mehal, Wajahat Z; Sheikh, Shehzad Z; Gorelik, Leonid et al. (2005) TGF-beta signaling regulates CD8+ T cell responses to high- and low-affinity TCR interactions. Int Immunol 17:531-8
Safadi, Rifaat; Ohta, Masayuki; Alvarez, Carlos E et al. (2004) Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 127:870-82
Kuniyasu, Yuhshi; Marfani, Suhail Mohammed; Inayat, Irteza Bin et al. (2004) Kupffer cells required for high affinity peptide-induced deletion, not retention, of activated CD8+ T cells by mouse liver. Hepatology 39:1017-27