We have recently identified two new molecules of the B7 family, B7-H3 and B7-H4. Preliminary data from our laboratory indicate that B7-H3 engages an activation-induced receptor on T cells to provide a costimulatory signal for proliferation and differentiation. In contrast, engagement of a putative receptor for B7-H4 also in activated T cells leads to inhibition of T cell proliferation, cytokine secretion and cell cycle arrest. The overall goal of our study is to elucidate cellular and molecular mechanisms of B7-H3 and B7-H4 in immune regulation and to manipulate these pathways to facilitate treatment of cancers and graft-versus-host diseases (GVHD). The central hypothesis of this proposal is that manipulation of B7-H3 and B7-H4 pathways could positively enhance T cell immunity against cancers and negatively prevent GVHD. To test this hypothesis, we will first explore the effect mechanisms and therapeutic potentials of B7-H3 pathways. Soluble B7-H3 fusion protein and gene transfer will be used to enhance B7-H3 costimulation as therapeutic approaches for treatment of cancers in animal models. Furthermore, neutralizing monoclonal antibodies and gene targeting mice of B7-H3 will be employed to explore potential therapeutics for prevention of GVHD. In contrast, fusion protein and gene delivery of B7-H4 will be utilized to enhance B7-H4 signal to suppress allogeneic T cell responses as an approach to prevent GVHD; gene targeting and monoclonal antibodies will be used to block the suppressive effect of B7-H4 to enhance tumor immunity. In addition, we will use bioinformatics, expression cloning and mass spectrometry techniques to identify the novel receptor for B7-H3 and B7-H4. Finally, we will use our expertise in structural biology to develop structure-based engineering of these B7 molecules to enhance therapeutic efficacy. We anticipate that these studies will provide a foundation for the development of new approaches for the prevention and immunotherapy of cancers and GVHD.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098731-01
Application #
6561486
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Hecht, Toby T
Project Start
2003-01-21
Project End
2007-12-31
Budget Start
2003-01-21
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$289,361
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Luo, Liqun; Zhu, Gefeng; Xu, Haiying et al. (2015) B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets. PLoS One 10:e0130126
Zhu, Yuwen; Yao, Sheng; Iliopoulou, Bettina P et al. (2013) B7-H5 costimulates human T cells via CD28H. Nat Commun 4:2043
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
Yi, Kyung H; Chen, Lieping (2009) Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev 229:145-51
Azuma, Takeshi; Zhu, Gefeng; Xu, Haiying et al. (2009) Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data. PLoS Med 6:e1000166
Zhu, Gefeng; Augustine, Mathew M; Azuma, Takeshi et al. (2009) B7-H4-deficient mice display augmented neutrophil-mediated innate immunity. Blood 113:1759-67
Kryczek, Ilona; Wei, Shuang; Zhu, Gefeng et al. (2007) Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67:8900-5
Jun, Her; Seo, Su K; Jeong, Hye-Young et al. (2005) B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK). FEBS Lett 579:6259-64
Luo, Liqun; Chapoval, Andrei I; Flies, Dallas B et al. (2004) B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 173:5445-50

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