The objectives of this grant in the next funding period will be to analyze the immunoregulatory properties of placental protein 14 (PP14) in greater depth and to design and evaluate PP14 derivatives with immunotherapeutic potential. This competitive renewal application builds upon a body of work from our laboratory during the prior funding period that first demonstrated a direct PP14 inhibitory effect on T cells, established PP14's unique """"""""rheostatic"""""""" mechanism of action in elevating T cell receptor activation thresholds, developed the first recombinant derivatives of PP14, defined PP14's molecular binding potentials, and cloned and characterized animal PP14 homologues. Based upon our novel insights into PP14's functional properties, we now hypothesize that PP14 may explain some immunological phenomoena of pregnancy, such as the shift towards Th2 cytokine output and the clinical improvement documented in pregnant women suffering from certain autoimmune diseases. With this in mind, we intend to move towards PP14-based immunotherapeutics for inhibiting pathogenic T cells.
The specific aims are: 1) to define the phenotype and fate of lymphocytes inhibited by PP14; 2) to elucidate the molecular mechanisms of PP14-mediated T cell inhibition, with the goal of identifying critical membrane receptor(s) and intracellular cell signaling pathway(s) influenced by PP14; and 3) to design recombinant derivatives of PP14 with enhanced functions, and to explore their therapeutic use in autoimmune and alloimmune animal disease models. The proposed studies combine basic and applied features.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038960-07
Application #
6497076
Study Section
Pathology B Study Section (PTHB)
Program Officer
Nabavi, Nasrin N
Project Start
1996-02-15
Project End
2006-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
7
Fiscal Year
2002
Total Cost
$403,562
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ish-Shalom, Eliran; Gargir, Ari; Andre, Sabine et al. (2006) alpha2,6-Sialylation promotes binding of placental protein 14 via its Ca2+-dependent lectin activity: insights into differential effects on CD45RO and CD45RA T cells. Glycobiology 16:173-83
Mishan-Eisenberg, Galit; Borovsky, Zipora; Weber, Matthew C et al. (2004) Differential regulation of Th1/Th2 cytokine responses by placental protein 14. J Immunol 173:5524-30
Rachmilewitz, Jacob; Borovsky, Zipora; Riely, Gregory J et al. (2003) Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45. J Biol Chem 278:14059-65
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
Rachmilewitz, Jacob; Borovsky, Zipora; Mishan-Eisenberg, Galit et al. (2002) Focal localization of placental protein 14 toward sites of TCR engagement. J Immunol 168:2745-50
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
Rachmilewitz, J; Riely, G J; Huang, J H et al. (2001) A rheostatic mechanism for T-cell inhibition based on elevation of activation thresholds. Blood 98:3727-32
Riely, G J; Rachmilewitz, J; Koo, P H et al. (2000) alpha2-macroglobulin modulates the immunoregulatory function of the lipocalin placental protein 14. Biochem J 351 Pt 2:503-8
Rachmilewitz, J; Riely, G J; Tykocinski, M L (1999) Placental protein 14 functions as a direct T-cell inhibitor. Cell Immunol 191:26-33
Rachmilewitz, J; Tykocinski, M L (1998) Differential effects of chondroitin sulfates A and B on monocyte and B-cell activation: evidence for B-cell activation via a CD44-dependent pathway. Blood 92:223-9

Showing the most recent 10 out of 12 publications