Abstract

There is a need for effective therapies to suppress pathogenic immune responses in autoimmune and alloimmune diseases. Our specific interest is in therapies that use antigen-presenting cells (APCs) as cellular tools for antigen-specific T cell immunomodulation. The present grant stems from the seminal observation made first by us, and later by others, that APCs can be converted into inhibitory cells, designated as """"""""artificial veto cells (AVCs),"""""""" that can inhibit antigen-specific T cells. Our approach for engineering an AVC involves expressing (by protein transfer) a """"""""coinhibitor"""""""" on an APC surface; this coinhibitor (such as a recombinant CD8 protein), operating coordinately with MHC.antigen, sends an inhibitory signal to the T cell. The present proposal consists of three specific aims which provide experimental paths towards determining the optimal surface display for an AVC and deciphering molecular determinants of coinhibitor function.
These aims i nclude: (1) characterizing the interplay between coinhibitors and costimulators using protein transfer and Abs as tools; (2) AVC engineering by protein transfer of lipidated derivatives of CD95L (Fas ligand) and other coinhibitor candidates; and (3) using isolated IgSF domains as probes for novel cell surface intermolecular interactions, with a focus on connections between CD8 and MHC proteins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031044-09
Application #
6169649
Study Section
Special Emphasis Panel (ZRG2-ET-1 (01))
Program Officer
Quill, Helen R
Project Start
1992-07-01
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
9
Fiscal Year
2000
Total Cost
$295,479
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Razmara, Marjaneh; Hilliard, Brendan; Ziarani, Azadeh K et al. (2009) Fn14-TRAIL, a chimeric intercellular signal exchanger, attenuates experimental autoimmune encephalomyelitis. Am J Pathol 174:460-74
Razmara, Marjaneh; Hilliard, Brendan; Ziarani, Azadeh K et al. (2008) CTLA-4 x Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells. Int Immunol 20:471-83
Orbach, Ariel; Rachmilewitz, Jacob; Parnas, Miram et al. (2007) CTLA-4 . FasL induces early apoptosis of activated T cells by interfering with anti-apoptotic signals. J Immunol 179:7287-94
Tone, Yukiko; Kojima, Yoshitsugu; Furuuchi, Keiji et al. (2007) OX40 gene expression is up-regulated by chromatin remodeling in its promoter region containing Sp1/Sp3, YY1, and NF-kappa B binding sites. J Immunol 179:1760-7
Dranitzki-Elhalel, M; Huang, J H; Sasson, M et al. (2007) CD40.FasL inhibits human T cells: evidence for an auto-inhibitory loop-back mechanism. Int Immunol 19:355-63
Chen, Aoshuang; Zheng, Guoxing; Tykocinski, Mark L (2003) Quantitative interplay between activating and pro-apoptotic signals dictates T cell responses. Cell Immunol 221:128-37
Elhalel, Michal Dranitzki; Huang, Jui-Han; Schmidt, William et al. (2003) CTLA-4. FasL induces alloantigen-specific hyporesponsiveness. J Immunol 170:5842-50
Tykocinski, Mark L; Chen, Aoshuang; Huang, Jui-Han et al. (2003) New designs for cancer vaccine and artificial veto cells: an emerging palette of protein paints. Immunol Res 27:565-74
Moody, D Branch; Briken, Volker; Cheng, Tan-Yun et al. (2002) Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nat Immunol 3:435-42
Zheng, G; Chen, A; Sterner, R E et al. (2001) Induction of antitumor immunity via intratumoral tetra-costimulator protein transfer. Cancer Res 61:8127-34

Showing the most recent 10 out of 24 publications