Three projects and two cores make up this competing renewal program project grant application to study mechanisms of effect of novel immunotherapeutics used to treat animal models of autoimmune disease. The studies described within this application will study two novel immunotherapies (adoptive cellular gene therapy and DNA vaccination) in two animal models of autoimmune diseases (CIA and EAE) as well as attempt to understand the mechanism(s) of successful therapeutic intervention. These therapies are poised to enter clinical trials once mechanistic understanding of effect has been demonstrated. Adoptive cellular gene therapy (Project 1) using T cell hybridomas or dendritic cells as vehicles to deliver various regulatory proteins expressed as transgenes has been proposed.
Three specific aims i n this project will allow vector development and adaptation of vehicle technology from T cells to autologous dendritic cells as well as studies designed to understand the mechanisms of effect. Innovative therapy will also be studied using a novel model of the application of an immuno-inhibitory GpG-ODN in vaccination models, with a single base switch from CpG to GpG, that can effectively inhibit the immuno-stimulatory response of its CpG-ODN counterpart (Project 3). Moreover, this inhibitory GpG-ODN is capable of suppressing the disease severity of experimental autoimmune encephalomyelitis (EAE) in mice by apparently inducing a Th2 shift, much as DNA co-vaccination with genes encoding myelin and IL-4. Mechanistic analysis of therapeutic intervention in both models will be studied using mRNA microarray, proteomics and intracellular assays of protein expression (Project 2). It is hoped that the combination of these approaches, integrating state of the art technology, will speed mechanistic understanding, thus human trials. Well-described interactions among the three investigators during the past funding period as well as current innovative projects and appropriate use of the animal and administrative cores are outlined in the text.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI036535-12
Application #
7250297
Study Section
Special Emphasis Panel (ZAI1-NN-I (S1))
Program Officer
Esch, Thomas R
Project Start
1997-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
12
Fiscal Year
2007
Total Cost
$1,002,938
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Samusik, Nikolay; Good, Zinaida; Spitzer, Matthew H et al. (2016) Automated mapping of phenotype space with single-cell data. Nat Methods 13:493-6
Spitzer, Matthew H; Nolan, Garry P (2016) Mass Cytometry: Single Cells, Many Features. Cell 165:780-91
Frei, Andreas P; Bava, Felice-Alessio; Zunder, Eli R et al. (2016) Highly multiplexed simultaneous detection of RNAs and proteins in single cells. Nat Methods 13:269-75
Angelo, Michael; Bendall, Sean C; Finck, Rachel et al. (2014) Multiplexed ion beam imaging of human breast tumors. Nat Med 20:436-42
Gottlieb, Peter; Utz, Paul J; Robinson, William et al. (2013) Clinical optimization of antigen specific modulation of type 1 diabetes with the plasmid DNA platform. Clin Immunol 149:297-306
O'Gorman, William E; Dooms, Hans; Thorne, Steve H et al. (2009) The initial phase of an immune response functions to activate regulatory T cells. J Immunol 183:332-9
Sachs, Karen; Itani, Solomon; Carlisle, Jennifer et al. (2009) Learning signaling network structures with sparsely distributed data. J Comput Biol 16:201-12
Creusot, Remi J; Yaghoubi, Shahriar S; Chang, Pearl et al. (2009) Lymphoid-tissue-specific homing of bone-marrow-derived dendritic cells. Blood 113:6638-47
Sachs, K; Itani, S; Fitzgerald, J et al. (2009) Learning cyclic signaling pathway structures while minimizing data requirements. Pac Symp Biocomput :63-74
Creusot, Remi J; Yaghoubi, Shahriar S; Kodama, Keiichi et al. (2008) Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice. Clin Immunol 127:176-87

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