Abstract

The long-term goal of this renewal application is to determine how gamma/delta T cells and non-cytolytic alpha/beta T cells regulate tolerance to OVA as an exogenous antigen, an endogenous antigen and as a tumor antigen. Transgenic mice expressing OVA-specific TCR on CD8+ T cells (TCR-1) or CD4+ T cells (OT-11) and a variety of knockout mice will be used to explore the physiological signals that control development of tolerance.
The first aim i s to characterize non- cytolytic, CD8+ T cells from B6 mice expressing transgenic TCR-1 T cells and gamma/delta T cells cloned from intra-epithelial lymphocytes. Interactions between gamma/delta T cells and non- cytolytic, CD8+ T cells will be studied by adoptive transfer into gamma/delta TCR deficient mice. Recipients expressing transgenic, OT-11 T cells will be used to determine how non-cytolytic CD8+ T cells inhibit antibody responses. In the second aim, the function of gamma/delta T cells and non-cytolytic CD8+ T cells in OVA transgenic mice will be evaluated using TCR-1 mice. The hypothesis that E.G7-OVA induces tumor-specific tolerance will be tested in the third aim. If tolerance is found, the investigator will determine whether CD8+ T cells are deleted, anergic or display altered functions. The ability of E.G7-OVA tumors transfected with a co-stimulatory molecule to reverse tolerance will be tested. The cellular and molecular effects of noscapine on tumor-specific- tolerance and immunity will be identified. Results from these studies should provide the basis for developing clinical trials of noscapine in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070372-06
Application #
6376248
Study Section
Experimental Immunology Study Section (EI)
Project Start
1996-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2003-04-30
Support Year
6
Fiscal Year
2001
Total Cost
$241,655
Indirect Cost

  Institution

Name
Emory University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Zimring, James C; Kapp, Linda M; Yamada, Masahisa et al. (2005) Regulation of CD8+ cytolytic T lymphocyte differentiation by a cholinergic pathway. J Neuroimmunol 164:66-75
Kapp, Judith A; Kapp, Linda M; McKenna, Kyle C (2004) Gammadelta T cells play an essential role in several forms of tolerance. Immunol Res 29:93-102
Kapp, Judith A; Kapp, Linda M; McKenna, Kyle C et al. (2004) gammadelta T-cell clones from intestinal intraepithelial lymphocytes inhibit development of CTL responses ex vivo. Immunology 111:155-64
Zimring, James C; Levery, Steven B; Kniep, Bernhard et al. (2003) CD75s is a marker of murine CD8(+) suppressor T cells. Int Immunol 15:1389-99
Ma, H; Kapp, J A (2001) Peptide affinity for MHC influences the phenotype of CD8(+) T cells primed in vivo. Cell Immunol 214:89-96
Ma, H; Kapp, J A (2000) Antigenic epitopes regulate the phenotype of CD8+ CTL primed by exogenous antigens. J Immunol 164:5698-703
Ke, Y; Ye, K; Grossniklaus, H E et al. (2000) Noscapine inhibits tumor growth with little toxicity to normal tissues or inhibition of immune responses. Cancer Immunol Immunother 49:217-25
Dombrowski, K E; Ke, Y; Brewer, K A et al. (1998) Ecto-ATPase: an activation marker necessary for effector cell function. Immunol Rev 161:111-8
Ke, Y; Ma, H; Kapp, J A (1998) Antigen is required for the activation of effector activities, whereas interleukin 2 Is required for the maintenance of memory in ovalbumin-specific, CD8+ cytotoxic T lymphocytes. J Exp Med 187:49-57
Kapp, J A; Ke, Y (1997) The role of gammadelta TCR-bearing T cells in oral tolerance. Res Immunol 148:561-7

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