Type I diabetes mellitus (T1DM) is a devastating disorder resulting from autoimmune destruction of insulin-producing pancreatic beta cells. TIDM is T cell mediated;B cells are also essential. Our long term goal is to elucidate the mechanisms by which B lymphocytes migrate to and are retained at sites of autoimmune attack and to use this information to design therapeutic options to disrupt those pathways and alter the pathological process. The specific hypothesis is that chemokines recruit B cells to pancreatic islets, where they contribute inflammatory signals driving benign insulitis to overwhelming disease. We base that hypothesis on the observations that: 1) we find large, well-organized B cell infiltrates in the islets, 2) an experimental technique which redistributes B cells away from islets is protective, 3) B cell receptor specificity (BCR) profoundly impacts disease as well as islet localization of B cells.
The specific aims of this proposal are to: 1) identify the molecular signals that attract B lymphocytes to the islets of Non-Obese Diabetic mice and use this information to block B cell entry into the site of inflammation. We will investigate the effects of CXCL13 on B cell migration to the islets using transwell migration and adoptive transfer studies. In-vivo blockade of these signals to determine effects on native B cell localization and disease will follow. 2) Determine the effects of B cell specificity and activation status on entry into and retention in inflamed islets. We have engineered two NOD mouse lines expressing BCRs specific for insulin (disease-promoting), or a non-islet antigen (protective). We will compare the islet chemokine responses of naive, antigen-engaged, and T-cell-activated B cells from these mice using adoptive transfer, transwell migration, and confocal imaging. 3) Develop a mouse model of TIDM in which B cell chemoattraction is altered to further clarify the effects of B cell localization in this disease. These studies will identify the mechanims that mediate entry of B lymphocytes into a site of autoimmune attack and may identify novel targets of intervention in TIDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK070924-05
Application #
7579889
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2005-04-15
Project End
2010-09-30
Budget Start
2009-04-01
Budget End
2010-09-30
Support Year
5
Fiscal Year
2009
Total Cost
$124,950
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bonami, Rachel H; Sullivan, Allison M; Case, James B et al. (2014) Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. J Immunol 192:1459-70
Henry-Bonami, Rachel A; Williams, Jonathan M; Rachakonda, Amita B et al. (2013) B lymphocyte ""original sin"" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. J Immunol 190:5992-6003
Kendall, Peggy L; Case, James B; Sullivan, Allison M et al. (2013) Tolerant anti-insulin B cells are effective APCs. J Immunol 190:2519-26
Henry, Rachel A; Kendall, Peggy L (2010) CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice. J Immunol 185:1460-5
Henry, Rachel A; Kendall, Peggy L; Woodward, Emily J et al. (2010) Vkappa polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains. Immunogenetics 62:507-20
Moore, Daniel J; Zienkiewicz, Jozef; Kendall, Peggy L et al. (2010) In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes. PLoS One 5:e13235
Kendall, Peggy L; Moore, Daniel J; Hulbert, Chrys et al. (2009) Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene. J Immunol 183:6403-12
Kendall, Peggy L; Yu, Guowu; Woodward, Emily J et al. (2007) Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol 178:5643-51