The nonobese diabetic (NOD) mouse represents an excellent model for analyzing pathogenic mechanisms underlying autoimmune destruction of pancreatic beta cells. Our objectives are to elucidate the immunopathogenic basis underlying the failure of NOD T cells to develop tolerance to beta cell antigens, and to use gene therapy to restore more normal immunoregulation and thus prevent autoimmune diabetes. We have shown that pathogenesis initiates at the hematopoietic stem cell level since NOS bone marrow adoptively transfers disease into otherwise diabetes-resistant F1 radiation chimeras. We have established that although diabetes in NOD mice is under polygenic control, the MHC class II region of the unique H-2 haplotype encodes a major component of susceptibility. We have identified a number of defects in signaling between NOD antigen presenting cells (APC) and T cells. Some of these defects express as an aberrant development of marrow-derived macrophages (MO). We found that APC transgenically expressing an H-2-Ea class II transgene block the development of diabetogenic T cells from NOD marrow. This renewal proposal has three objectives. The first is to develop a gene therapy protocol t reverse the diabetogenic potential of NOD marrow. We propose to use retroviral vectors to transduce a protective H-2-Ea cDNA ligated to a genomic promoter into NOD hematopoietic stem cells. We shall test whether APC derived from such retrovirally-transduced stem cells express sufficient I-E molecules to block diabetes. Our second specific aim will employ competitive bone marrow chimeras and fetal thymic organ culture to test whether aberrant MO development also underlies failure of NOD T cells to become tolerant to beta cells. The third specific aim is to use intrathymic injection of candidate Beta cell autoantigens into adolescent NOD mice as a means for identifying the primary autoantigens to which tolerance must be induced to circumvent diabetogenesis. Successful completion of these studies will not only provide a gene therapy model for autoimmune insulin dependent diabetes in humans, but may also elucidate immunophenotype that identify prediabetic humans who may be the logical recipients of this therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DK027722-14
Application #
2138043
Study Section
Pathology A Study Section (PTHA)
Project Start
1981-05-01
Project End
1999-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
14
Fiscal Year
1994
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
Leiter, Edward H; Lee, Chul-Ho (2005) Mouse models and the genetics of diabetes: is there evidence for genetic overlap between type 1 and type 2 diabetes? Diabetes 54 Suppl 2:S151-8
Mathews, C E; Leiter, E H; Spirina, O et al. (2005) mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia 48:261-7
Lee, Chul-Ho; Reifsnyder, Peter C; Naggert, Jurgen K et al. (2005) Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis. Diabetes 54:2525-32

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