The Non-Obese Diabetic (NOD) mouse presents an excellent model for analyzing pathogenetic mechanisms underlying autoimmune destruction of pancreatic beta (B) cells. We have established that expression of NOD diabetogenic genes at the level of bone marrow derived effector cells is sufficient to adoptively transfer diabetes into otherwise diabetes-resistant F1 radiation chimeras. Immunoregulatory defects in signaling between accessory cells and T cells have been identified in NOD mice, and include defective activation of T suppressor cells accompanied by impaired IL-1 and IL-2 release. Proposed transplantation experiments will assess the pathogenic role of thylmocyte interactions with cells in the thymic microenvironment expressing the unique NOD H-2 gene products. A new NOD congenic strain carrying the recessive mutation """"""""severe combined immunodeficiency"""""""" (scid) has been created to allow evaluation of the pathogenic contributions of defined subsets of NOD T cells. The scid mutation prevents development of endogenous T and B lymphocytes such that these mice will be ideal for the T cell adoptive transfer studies proposed. NOD-scid mice will also permit testing whether defects in cytokine release cascades and failure to actively suppress autoreactive T cells are consequences of the unique I-AB gene product on accessory cells. Transplantation into reconstituted NOD-scid mice of NOD islets cultured in the presence or absence of gamma interferon (to induce Class I and Class II MHC antigens on B cells) will permit critical testing of the pathogenic significance of expression of the Ia antigen on B cells. Finally, to test the pathogenic consequences of high levels of retrovirus (intracisternal type A) expression in B cells, transgenic mice will be constructed to target this retroviral gene coupled with an insulin gene promoter into B cells of C57BL/6J mice that normally cannot express this endogenous retroviral genome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027722-10
Application #
3228446
Study Section
Pathology A Study Section (PTHA)
Project Start
1981-05-01
Project End
1994-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Chen, Jing; Gusdon, Aaron M; Piganelli, Jon et al. (2011) mt-Nd2(a) Modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic ?-cell. Diabetes 60:355-9
Chen, Yi-Guang; Scheuplein, Felix; Driver, John P et al. (2011) Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice. J Immunol 186:4278-84
Chen, Jing; Lu, Ying; Lee, Chul-Ho et al. (2008) Commonalities of genetic resistance to spontaneous autoimmune and free radical--mediated diabetes. Free Radic Biol Med 45:1263-70
Reifsnyder, Peter; Schott, William; Pomerleau, Darcy et al. (2008) Bone marrow expressing a diabetes resistance MHC class II allele: diabetes deviation by chronic immune stimulation. Novartis Found Symp 292:32-46;discussion 46-9, 122-9, 2
Chen, Jing; Chen, Yi-Guang; Reifsnyder, Peter C et al. (2006) Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ADP-ribosyltransferase 2-dependent fashion. J Immunol 176:4590-9
Lee, Chul-Ho; Chen, Yi-Guang; Chen, Jing et al. (2006) Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis. Diabetes 55:171-8
Chen, Yi-Guang; Chen, Jing; Osborne, Melissa A et al. (2006) CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice. J Immunol 177:2939-47
Krebs, Christian; Adriouch, Sahil; Braasch, Fenja et al. (2005) CD38 controls ADP-ribosyltransferase-2-catalyzed ADP-ribosylation of T cell surface proteins. J Immunol 174:3298-305
Chen, Jing; Reifsnyder, Peter C; Scheuplein, Felix et al. (2005) ""Agouti NOD"": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells. Mamm Genome 16:775-83
Reifsnyder, P C; Li, R; Silveira, P A et al. (2005) Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice. Genes Immun 6:528-38

Showing the most recent 10 out of 86 publications