We hypothesize that autoimmune diseases progress through several (at least two) """"""""checkpoints"""""""", an early inflammatory and late phase destructive disease. We believe it might be possible to design common """"""""prevention"""""""" strategies to arrest disease progression in one or both of these phases by the following. (1) Autoantigen reactive CD4+ T cells transduced with retroviral vectors to express """"""""regulatory proteins"""""""" may provide tissue specific immunotherapy through the expression of the regulatory proteins at the site of autoimmune inflammation. (2) FcR non-binding anti-CD3 and anti-TNF antibodies might block disease progression. We plan to study the non-obese diabetic (NOD) mouse, that spontaneously develops insulin-dependent diabetes mellitus (IDDM) and shows many of the characteristics of human IDDM, and collagen induced arthritis (CIA) in the DBA/l mouse model, which shares certain characteristics of human rheumatoid arthritis (RA), to attempt these """"""""disease prevention"""""""" strategies. We will use the antigen specific properties of autoantigen reactive T cells to develop an adoptive immunotherapy protocol to study the potential of one (or combinations) of various """"""""regulatory"""""""" proteins to prevent both of these diseases. We will study the """"""""anti-inflammatory"""""""" cytokines, IL-10 and IL-4, an antagonist of a """"""""pro-inflammatory"""""""" cytokine receptor, IL-12 p40, and compare local delivery by retroviral transduction of auto antigen specific T cells with SC fV constructs of anti-CD3 and anti-TNF antibodies, to systemic use of the parent antibodies, in these two animal models, singly and in combinations. Additionally, we plan to analyze potential mechanistic effects of anti-CD3 on antigen reactive T cells compared to co-stimulatory blockade by looking at the expression of a novel anergy specific gene, GRAIL.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DK061934-02
Application #
6618189
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2002-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Rosenberg, Jacob M; Price, Jordan V; Barcenas-Morales, Gabriela et al. (2016) Protein microarrays identify disease-specific anti-cytokine autoantibody profiles in the landscape of immunodeficiency. J Allergy Clin Immunol 137:204-213.e3
Teo, Pearline Zhaoying; Utz, Paul J; Mollick, Joseph A (2012) Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1. Cancer Immunol Immunother 61:2295-309
Kattah, Nicole H; Kattah, Michael G; Utz, Paul J (2010) The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev 233:126-45
Graham, Kareem L; Lee, Lowen Y; Higgins, John P et al. (2010) Treatment with a toll-like receptor inhibitory GpG oligonucleotide delays and attenuates lupus nephritis in NZB/W mice. Autoimmunity 43:140-55
Thibault, Donna L; Graham, Kareem L; Lee, Lowen Y et al. (2009) Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther 11:R112
Yip, Linda; Su, Leon; Sheng, Deqiao et al. (2009) Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nat Immunol 10:1026-33
Kattah, Michael G; Coller, John; Cheung, Regina K et al. (2008) HIT: a versatile proteomics platform for multianalyte phenotyping of cytokines, intracellular proteins and surface molecules. Nat Med 14:1284-9
Drouvalakis, Katerina A; Bangsaruntip, Sarunya; Hueber, Wolfgang et al. (2008) Peptide-coated nanotube-based biosensor for the detection of disease-specific autoantibodies in human serum. Biosens Bioelectron 23:1413-21
Kodama, Keiichi; Butte, Atul J; Creusot, Remi J et al. (2008) Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. Clin Immunol 129:195-201
Chan, Steven M; Olson, Janelle A; Utz, Paul J (2006) Single-cell analysis of siRNA-mediated gene silencing using multiparameter flow cytometry. Cytometry A 69:59-65

Showing the most recent 10 out of 48 publications