In both humans and the NOD mouse model, insulin dependent diabetes (IDDM) results from autoimmune destruction of pancreatic beta cells by T lymphocytes. Thus far, it is not known which specific subpopulations of antigen presenting cells (APCs - B lymphocytes, macrophages or dendritic cells) contribute to the development and activation of diabetogenic T lymphocytes. Preliminary data show that B lymphocytes play an essential role, since disease incidence is completely inhibited in a stock of NOD mice made B lymphocyte deficient by congenic transfer of a functionally disrupted Ig-mu allele (NOD.Ig-mu null). Preliminary data also show that B lymphocytes are the only APC population that can immunologically process glutamic acid decarboxylase (GAD), which may be the earliest beta cell antigen targeted by autoreactive T lymphocytes in NOD mice. In addition, an epitope in GAD that is reported to be preferentially presented by APC to autoreactive T lymphocytes in both NOD mice and human IDDM patients is highly homologous with a segment of the Coxsackie virus P2-C protein. Thus Coxsackie virus infection may provide a cross-reactive antigenic trigger for the activation of diabetogenic GAD autoreactive T lymphocytes in genetically susceptible individuals. Furthermore, normally quiescent, diabetogenic T lymphocytes may still develop in B lymphocyte deficient NOD.Ig-mu null mice if other subpopulations of APC have the capacity to generate mimics of beta cell autoantigens from infectious agents such as Coxsackie virus. To test this hypothesis, the investigators will pursue two major aims. The first is to determine whether B lymphocytes are required for the development as well the functional activation of T lymphocytes capable of responding to various GAD-derived peptides in NOD mice. The second is to determine if IDDM resistance in NOD.Ig-mu null mice can be abrogated by priming with GAD derived peptides or a Coxsackie viral infection that may bypass the normal requirement for B lymphocytes to generate antigenic epitopes from native GAD. These studies will provide insights to the basic mechanisms by which beta cell antigens are presented to autoreactive T lymphocytes in IDDM, and how these processes may be influenced by a Coxsackie viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI041469-03
Application #
2887472
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Akolkar, Beena
Project Start
1997-06-01
Project End
2000-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Mathews, Clayton E; Langley, Stephen H; Leiter, Edward H (2002) New mouse model to study islet transplantation in insulin-dependent diabetes mellitus. Transplantation 73:1333-6
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Johnson, E A; Silveira, P; Chapman, H D et al. (2001) Inhibition of autoimmune diabetes in nonobese diabetic mice by transgenic restoration of H2-E MHC class II expression: additive, but unequal, involvement of multiple APC subtypes. J Immunol 167:2404-10
Serreze, D V; Chapman, H D; Post, C M et al. (2001) Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. J Immunol 166:1352-9
Mathews, C E; Graser, R T; Savinov, A et al. (2001) Unusual resistance of ALR/Lt mouse beta cells to autoimmune destruction: role for beta cell-expressed resistance determinants. Proc Natl Acad Sci U S A 98:235-40
Serreze, D V; Post, C M; Chapman, H D et al. (2000) Interferon-gamma receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice. Diabetes 49:2007-11

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