Type 1 diabetes (T1D) is characterized by the CD4+ and CD8 + T cell mediated destruction of the insulin producing ( cells. We and others have demonstrated that antigen-specific based immunotherapies can be effective at suppressing early and late stages of preclinical T1D in nonobese diabetic (NOD) mice. However, little is known regarding the efficacy of antigen-specific immunotherapy once overt diabetes is established. This is an important issue for islet transplantation and the prevention of autoimmune mediated destruction of the graft in a diabetic recipient. Recently we found that administration of plasmid DNAs (pDNAs) encoding the beta cell autoantigen GAD65, IL-4 and IL-10 protected islet grafts from recurrent autoimmune destruction in diabetic NOD recipients. Furthermore, varying the conditions of pDNA vaccination resulted in different degrees of islet graft protection. Interestingly, the type and frequency of immunoregulatory T effectors induced via pDNA administration correlated with the efficacy of islet graft protection. The current application proposes to define the effector cells and mechanisms that immunoregulate ( cell autoimmunity at the clinical end stage of T1D, and mediate long-term islet graft survival. In this way, insight will be gained into the key events that influence autoimmune destruction of islet grafts, in addition to obtaining a better understanding of the parameters which may influence the efficacy of antigen-specific based immunotherapy in a clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058014-05
Application #
7404397
Study Section
Special Emphasis Panel (ZRG1-ALY (02))
Program Officer
Esch, Thomas R
Project Start
2004-06-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2008
Total Cost
$338,790
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Yi, Zuoan; Li, Li; Garland, Alaina et al. (2012) IFN-ýý receptor deficiency prevents diabetes induction by diabetogenic CD4(+) T cells but not CD8(+) T cells. Eur J Immunol :
Yi, Zuoan; Li, Li; Garland, Alaina et al. (2012) IFN-? receptor deficiency prevents diabetes induction by diabetogenic CD4+, but not CD8+, T cells. Eur J Immunol 42:2010-8
Goudy, Kevin S; Johnson, Mark C; Garland, Alaina et al. (2011) Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J Immunol 186:3779-86
Goudy, Kevin S; Johnson, Mark C; Garland, Alaina et al. (2011) Reduced IL-2 expression in NOD mice leads to a temporal increase in CD62Llo FoxP3+ CD4+ T cells with limited suppressor activity. Eur J Immunol 41:1480-1490
Johnson, Mark C; Wang, Bo; Tisch, Roland (2011) Genetic vaccination for re-establishing T-cell tolerance in type 1 diabetes. Hum Vaccin 7:27-36
Li, Li; He, Qiuming; Garland, Alaina et al. (2009) beta cell-specific CD4+ T cell clonotypes in peripheral blood and the pancreatic islets are distinct. J Immunol 183:7585-91
Li, Chengwen; Hirsch, Matt; DiPrimio, Nina et al. (2009) Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo. J Virol 83:6817-24
Li, Li; Yi, Zuoan; Wang, Bo et al. (2009) Suppression of ongoing T cell-mediated autoimmunity by peptide-MHC class II dimer vaccination. J Immunol 183:4809-16
Li, Chengwen; Goudy, Kevin; Hirsch, Matt et al. (2009) Cellular immune response to cryptic epitopes during therapeutic gene transfer. Proc Natl Acad Sci U S A 106:10770-4

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