The overall objective of this application is to define mechanisms by which MHC class I loci contribute to diabetogenesis in NOD mice. Despite the fact that pancreatic Beta cells from NOD mice express high levels of MHC class 1, and that CD8+ T cells are required to initiate disease, little attention has been focused on the mechanisms by which the class I alleles of the H-2g7 haplotype interact with the genes within the unusual class 11 region to effect diabetogenesis.
The first aim to be addressed is whether MHC class I expression is required to mediate the selection and targeting of Beta cell autoreactive T cells in NOD mice. These questions will be evaluated through a series of experiments utilizing a stock of NOD mice made class I deficient by the presence of a disrupted Beta2-microglobulin (Beta2m) gene. In previously published work the applicant has demonstrated that antigen presenting cells (APC) expressing a diabetes resistant MHC can block the development of diabetogenic T cells from NOD bone marrow.
The second aim of this proposal is to determine if the ability of a diabetes resistant MHC haplotype to block the development of diabetogenic T cells is retained in the absence of class I expression. Stocks of MHC class I deficient NOD mice expressing class II alleles from diabetes resistant MHC haplotypes will be generated to achieve this aim.
The third aim focuses on the applicant's finding that the ability of NOD APC to mediate clonal deletion of autoreactive CD8+ T cells may be impaired since MHC class I expression is aberrantly down- regulated in a tissue specific fashion in IFNgamma treated macrophages from NOD mice, but not in macrophages from diabetes resistant H-2g7 identical NOR mice. Segregation analysis of (NOD x NOR)F2 progeny will delineate which of the four chromosomal regions distinguishing NOD from NOR mice contribute to defective trans-regulation of MHC class I expression, and determine if this defect contributes to diabetogenesis. These studies may aid in the identification of new genetic and immunophenotypic markers for susceptibility to autoimmune insulin dependent diabetes in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29DK046266-05S1
Application #
2795974
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
1993-06-01
Project End
1999-11-30
Budget Start
1997-06-01
Budget End
1999-11-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Presa, Maximiliano; Racine, Jeremy J; Dwyer, Jennifer R et al. (2018) A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice. J Immunol 201:1907-1917
Ratiu, Jeremy J; Racine, Jeremy J; Hasham, Muneer G et al. (2017) Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes. J Immunol 198:4255-4267
Driver, John P; Racine, Jeremy J; Ye, Cheng et al. (2017) Interferon-? Limits Diabetogenic CD8+ T-Cell Effector Responses in Type 1 Diabetes. Diabetes 66:710-721
Lin, Bixuan; Ciecko, Ashley E; MacKinney, Erin et al. (2017) Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice. Immunogenetics 69:193-198
Wang, Qiming; Racine, Jeremy J; Ratiu, Jeremy J et al. (2017) Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy. J Immunol 199:3757-3770
Mahmoud, Tamer I; Wang, Jingya; Karnell, Jodi L et al. (2016) Autoimmune manifestations in aged mice arise from early-life immune dysregulation. Sci Transl Med 8:361ra137
Leeth, Caroline M; Racine, Jeremy; Chapman, Harold D et al. (2016) B-lymphocytes expressing an Ig specificity recognizing the pancreatic ß-cell autoantigen peripherin are potent contributors to type 1 diabetes development in NOD mice. Diabetes 65:1977-1987
Tsaih, S-W; Presa, M; Khaja, S et al. (2015) A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells. Genes Immun 16:221-30
Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E et al. (2015) The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice. J Immunol 195:3011-9
Simecek, Petr; Churchill, Gary A; Yang, Hyuna et al. (2015) Genetic Analysis of Substrain Divergence in Non-Obese Diabetic (NOD) Mice. G3 (Bethesda) 5:771-5

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