We have recently identified B7-H1, a new member of the B7 costimulatory molecule family. Preliminary data from our laboratory demonstrated that B7-H1 engages a receptor of T cells to provide an initial signal for costimulation of T cell growth in vitro and promote cell-mediated and humoral immune responses to antigens in vivo. However, the majority of human cancers examined so far express high levels of B7-H1 and engagement of activated T cells by tumor-associated B7-H1 promotes programmed cell death. The overall goal of our study is to elucidate cellular and molecular mechanisms of B7-H1 in immune regulation and to manipulate this pathway for treatment of autoimmune diseases and cancers. The central hypothesis of this proposal is that B7-H1 regulates T cell responses in autoimmune diseases and cancers in a positive and negative fashion through different receptors. To test this hypothesis, we will use bioinformatics, expression cloning and mass spectrometry techniques to identify the novel receptor of B7-H1. In addition, we will utilize B7-H1 deficient and transgenic mouse models to elucidate immunological functions of B7-H1 in vivo. We will also evaluate the effect of B7-H1 in graft versus host disease (GVHD) models for potential treatment of autoimmune diseases. Finally, we will examine the mechanisms of tumor-associated B7-H1 in evasion of active and adoptive immunity in mouse tumor models. It is anticipated that these studies will provide a foundation for the development of new approaches for the prevention and immunotherapy of autoimmune diseases, transplantation rejection and cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097085-04
Application #
6951367
Study Section
Special Emphasis Panel (ZRG1-SSS-H (03))
Program Officer
Howcroft, Thomas K
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$363,788
Indirect Cost
Name
Johns Hopkins University
Department
Dermatology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Flies, Dallas B; Wang, Shengdian; Xu, Haiying et al. (2011) Cutting edge: A monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol 187:1537-41
Zhu, Yuwen; Yao, Sheng; Chen, Lieping (2011) Cell surface signaling molecules in the control of immune responses: a tide model. Immunity 34:466-78

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