Abstract

The overall goal of this proposal is to prevent the development of autoimmune diabetes by using multivalent MHC class II/peptide chimeras of high valency. The mechanisms and consequences of manipulating the immune system by multivalent MHC II/peptide chimeras will also be investigated.
The specific aims are: (1) to determine the protective capacity of soluble, multivalent MHC II/peptide chimeras in autoimmune diabetes as compared to bivalent MHC II/peptide chimera, (2) to study the cellular mechanisms of long-term protection in mice treated with these chimeric molecules , and (3) to study the TR-cell signaling events in mice protected against diabetes by these chimeric molecules. The proposed study will be carried out in a double transgenic mouse model for Type I Diabetes. Satisfactory results will lead to the generation of a human DEF-like molecule (hu- DEF) consisting of the HLA-DR*0401 allele, and the most common diabetogenic peptide in humans, GAD-, and pro-insulin- derived peptides. The therapeutic efficacy of hu-CEF will be evaluated in Tg mice (murine MHcalphabeta class II-/-, human HLA-DR* 0301 and -DR*0401 +/+) after immunization or not with GAD65 peptide, and then adoptively transferred with T-cells from HLA-DR-matched patients with IDDM, or from their at-high risk relatives.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061927-06
Application #
6931625
Study Section
Special Emphasis Panel (ZAI1-PTM-I (S1))
Program Officer
Akolkar, Beena
Project Start
2001-09-30
Project End
2007-12-31
Budget Start
2005-09-01
Budget End
2007-12-31
Support Year
6
Fiscal Year
2005
Total Cost
$150,600
Indirect Cost

  Institution

Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Rockville
State
MD
Country
United States
Zip Code
20817

  Publications

Lin, Marvin; Stoica-Nazarov, Cristina; Surls, Jacqueline et al. (2010) Reversal of type 1 diabetes by a new MHC II-peptide chimera: ""Single-epitope-mediated suppression"" to stabilize a polyclonal autoimmune T-cell process. Eur J Immunol 40:2277-88
Duncan, Beverly; Nazarov-Stoica, Cristina; Surls, Jacqueline et al. (2010) Double negative (CD3+ 4- 8-) TCR alphabeta splenic cells from young NOD mice provide long-lasting protection against type 1 diabetes. PLoS One 5:e11427
Nazarov-Stoica, Cristina; Surls, Jacqueline; Bona, Constantin et al. (2009) CD28 signaling in T regulatory precursors requires p56lck and rafts integrity to stabilize the Foxp3 message. J Immunol 182:102-10
Brumeanu, Teodor-D; Preda-Pais, Anca; Stoica, Cristina et al. (2007) Differential partitioning and trafficking of GM gangliosides and cholesterol-rich lipid rafts in thymic and splenic CD4 T cells. Mol Immunol 44:530-40
Brumeanu, Teodor-D; Goldstein, Robert; Casares, Sofia (2006) Down-regulation of autoreactive T-cells by HMG CoA reductase inhibitors. Clin Immunol 119:1-12
Preda-Pais, Anca; Stan, Alexandru C; Casares, Sofia et al. (2005) Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes. J Autoimmun 25:21-32
Preda, Ioana; McEvoy, Robert C; Lin, Marvin et al. (2005) Soluble, dimeric HLA DR4-peptide chimeras: an approach for detection and immunoregulation of human type-1 diabetes. Eur J Immunol 35:2762-75
George, Sunil K; Preda, Ioana; Avagyan, Serine et al. (2004) Immunokinetics of autoreactive CD4 T cells in blood: a reporter for the ""hit-and-run"" autoimmune attack on pancreas and diabetes progression. J Autoimmun 23:151-60
Thomas, Sunil; Preda-Pais, Anca; Casares, Sofia et al. (2004) Analysis of lipid rafts in T cells. Mol Immunol 41:399-409
Thomas, Sunil; Kumar, Rajeev S; Brumeanu, Teodor-D (2004) Role of lipid rafts in T cells. Arch Immunol Ther Exp (Warsz) 52:215-24

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