DNA vaccination is an effective means of protecting experimental animals against infectious pathogens and cancer, and has more recently been used to prevent and reverse autoimmune disease. We have demonstrated that vaccination with DNA encoding TCR Vbeta elements, or with DNA sequences encoding myelin antigens can prevent or reverse experimental autoimmune encephalomyelitis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by T cell-mediated destruction of the insulin-secreting Beta cells in the pancreas. The NOD mouse is an animal model of IDDM in which several autoantigens, including insulin, have been identified. In preliminary studies we have demonstrated that vaccination of NOD mice with DNA encoding an immunodominant peptide of insulin-residues 9-23 of the B chain-protects the animals from developing diabetes. Animals injected intramuscularly with a bacterial plasmid encoding the insulin B peptide show lower disease incidence and delayed onset of disease. Protection is mediated by insulin B (9-23)-specific downregulation of IFN-g. DNA immunization is explored here as a potential therapy in the treatment of autoimmune diabetes. We will rely on our growing experience with DNA vaccination in the prevention and treatment of EAE. These studies will complement the sections on therapy with genes introduced by retroviral vectors in the sections on in vitro gene transfer in Dr. Fathman's project, and studies of epitope spreading using a proteomic approach in Dr. Utz' project. In particular, can we predict efficacious cDNAs using the autoantibody screen with peptide microarrays described in Project 3? These studies will attempt to correlate prevention with epitope selection in EAE as well as the studies described above on IDDM.
In Aim 1, Reversal of Hyperglycemia, we will investigate whether diabetes in the NOD mouse can be reversed beginning immunization after the onset of glucosuria using DNA immunization to insulin residues 9-23 of the B chain.
In Aims 2 and 3 we will utilize IL-4 or IL-12 p40, or NGF as adjuvants with cDNA vaccination.
In Aim 4 we will test DNA vaccination with genes encoding multiple islet cell antigens, including insulin, GAD and hsp65.
In Aim 5 we will use protein microarrays to identify potential cDNA vaccination candidates. These studies may lead to new therapies for prevention and treatment of autoimmune disease in man.

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 #
6618190
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
Kanter, Jennifer L; Narayana, Sirisha; Ho, Peggy P et al. (2006) Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 12:138-43

Showing the most recent 10 out of 48 publications