T cell mediated autoimmune IDDM results from interactions between multiple susceptibility (Idd) genes located within and outside of the MHC. In NOD mice some of these polygenic interactions engender diabetogenic T cell development by reducing the ability of hematopoietically derived antigen presenting cells (APC) to activate various immunoregulatory functions. Subpopulations of APC include B-lymphocytes, macrophages, and dendritic cells. To partially address which APC subpopulations contribute to IDDM, the investigators produced NOD mice made deficient in B lymphocytes by a functionally inactivated Ig mu gene. These B lymphocyte deficient NOD.Ig mu null mice are IDDM resistant. Their overall objective is to delineate the mechanism(s) by which B lymphocytes contribute to the development of T cell mediated autoimmune 1DDM. They have found one mechanism that B lymphocytes contribute to IDDM is as a subpopulation of APC with a preferential ability to present certain pancreatic B cell antigens to autoreactive MHC class II restricted T cells.
Specific aim 1 is to determine if the B lymphocytes mediating this process must express immunoglobulin (Ig) molecules capable of specifically capturing B cell autoantigens, and if so, do these diabetogenic APC arise through tolerance induction defects. These issues will be addressed through use of NOD mice expressing rearranged Ig transgenes. Another unknown factor is if NOD B lymphocytes also manifest any Idd gene controlled defects in APC mediated tolerance induction that underlie the initial development of diabetogenic T cells. Expression of resistance variants of certain MHC Idd genes on all APC subtypes blocks the development or functional activation of diabetogenic T cells.
Aim 2 is to determine if particular sets of MHC genes that confer IDDM resistance must be expressed on specific APC subtypes to render NOD T cells tolerant to pancreatic B cell antigens. These studies will utilize NOD mice and related strains that express IDDM resistance variants of various MHC genes on specific APC subsets. Non-MHC genes also contribute to the diabetogenic APC activity of NOD B lymphocytes.
Specific aim 3 is to determine the mechanisms by which non-MHC genes contribute to the development of B-lymphocytes with diabetogenic APC activity in NOD mice. This issue will be addressed through a chimeric system in which NOD T cells can only mature and function in the presence of selected B lymphocyte populations. Collectively, the proposed studies will delineate mechanisms by which B lymphocytes make critical contributions to the development of T cell mediated autoimmune IDDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051090-09
Application #
6757986
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Spain, Lisa M
Project Start
1996-06-01
Project End
2005-12-31
Budget Start
2004-07-01
Budget End
2005-12-31
Support Year
9
Fiscal Year
2004
Total Cost
$330,000
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Chen, Y-G; Tsaih, S-W; Serreze, D V (2012) Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type. Genes Immun 13:164-74
Driver, John P; Chen, Yi-Guang; Zhang, Weidong et al. (2011) Unmasking genes in a type 1 diabetes-resistant mouse strain that enhances pathogenic CD8 T-cell responses. Diabetes 60:1354-9
Niens, Marijke; Grier, Alexandra E; Marron, Michele et al. (2011) Prevention of ""Humanized"" diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes 60:1229-36
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
Serreze, David V; Chapman, Harold D; Niens, Marijke et al. (2011) Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies. Diabetes 60:2914-21
Driver, John P; Scheuplein, Felix; Chen, Yi-Guang et al. (2010) Invariant natural killer T-cell control of type 1 diabetes: a dendritic cell genetic decision of a silver bullet or Russian roulette. Diabetes 59:423-32
Scheuplein, Felix; Rissiek, Björn; Driver, John P et al. (2010) A recombinant heavy chain antibody approach blocks ART2 mediated deletion of an iNKT cell population that upon activation inhibits autoimmune diabetes. J Autoimmun 34:145-54
Mangada, Julie; Pearson, Todd; Brehm, Michael A et al. (2009) Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice. Diabetes 58:165-73
Chen, Yi-Guang; Scheuplein, Felix; Osborne, Melissa A et al. (2008) Idd9/11 genetic locus regulates diabetogenic activity of CD4 T-cells in nonobese diabetic (NOD) mice. Diabetes 57:3273-80
Chaparro, Rodolfo Jose; Burton, Amanda R; Serreze, David V et al. (2008) Rapid identification of MHC class I-restricted antigens relevant to autoimmune diabetes using retrogenic T cells. J Immunol Methods 335:106-15

Showing the most recent 10 out of 52 publications