Both mucosal immunity and tolerance are crucial for maintaining the integrity of the self. On the one hand, the mucosae are the major ports of entry for pathogens that ought to be expelled; on the other hand, the gut contains enormous amounts of dietary antigens that must be tolerated. The investigator's long-term goal is to elucidate the mechanisms of mucosal immunity and tolerance. This application is based on the investigator's recent observation that the costimulatory molecule B7 is constitutively expressed in mucosal lymphoid tissues, and that blocking B7 costimulation prevents the induction of mucosal tolerance. The working hypothesis is that the levels of B7 expression at the mucosa may dictate whether immunity or tolerance develops following mucosal administration of antigens and that B7:CTLA4 interaction may play pivotal roles in the development of mucosal tolerance.
Two specific aims will be investigated. 1) What are the roles of B7 in mucosal immunity and tolerance? The levels of B7 expressed at the mucosa can be reduced by specific blockage, or increased by adenoviral vector-mediated B7 gene transfer. In this aim, the investigator will examine whether different levels of B7 affect the fates of specific T-cells at the mucosa. The question of whether """"""""follicular T-cell exclusion"""""""" occurs in the Peyer's patch during mucosal tolerance will also be examined, and, if so, whether it can be abrogated by transient upregulation of B7. The fates of antigen-specific T-cells will be tracked in vivo using a T-cell receptor transgenic model. 2) What are the roles of CTLA4 in mucosal immunity and tolerance? The investigator has recently found that CTLA4 blockade at the time of mucosal antigen administration prevented the induction of T-cell tolerance. In this aim, the investigator proposes to examine the kinetics of CTLA4 expression during mucosal tolerance using the adoptive TcR transgenic model. The investigator will then generate CTLA4 deficient TcR transgenic mice by crossing CTLA4 deficient mice with TcR transgenic mice. The CTLA4 deficient ovalbumin-specific T-cells will then be adoptively transferred into normal mice and their reactivity to mucosal antigens examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041060-05
Application #
6510720
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Rothermel, Annette L
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$264,258
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, Yiguang; Chen, Youhai (2003) Cytokines, lymphocyte homeostasis and self tolerance. Adv Exp Med Biol 520:66-72
Chen, Yiguang; Ma, Yuanfang; Chen, Youhai (2002) Roles of cytotoxic T-lymphocyte-associated antigen-4 in the inductive phase of oral tolerance. Immunology 105:171-80
Lamhamedi-Cherradi, S E; Chen, Y (2001) Fas (CD95, Apo-1) ligand gene transfer. J Clin Immunol 21:24-9
Song, K; Chen, Y; Goke, R et al. (2000) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 191:1095-104
Chen, Y; Song, K; Eck, S L (2000) An intra-Peyer's patch gene transfer model for studying mucosal tolerance: distinct roles of B7 and IL-12 in mucosal T cell tolerance. J Immunol 165:3145-53
Goke, R; Goke, A; Goke, B et al. (2000) Regulation of TRAIL-induced apoptosis by transcription factors. Cell Immunol 201:77-82
Hilliard, B; Samoilova, E B; Liu, T S et al. (1999) Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J Immunol 163:2937-43
Samoilova, E B; Horton, J L; Chen, Y (1998) Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell Immunol 188:118-24
Samoilova, E B; Horton, J L; Hilliard, B et al. (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161:6480-6