Insulin dependent diabetes mellitus (IDDM) in humans and NOD mice is an autoimmune disease caused by the selective destruction of pancreatic beta cells by autoreactive T lymphocytes. In addition to the well characterized loss of T-cell tolerance to islet autoantigens, the presence of anti-islet antibodies highlights a concomitant dysregulation of B-cell tolerance to these antigens. The requisite role of B-cells in diabetogenesis has recently been established in studies of B-cell deficient NOD mice which were found to be protected from insulitis and diabetes. Whether the role of B-cells in NOD diabetogenesis is mediated by the activated autoreactive B-cells and whether this role involves antigen presentation by B-cells in unknown. The investigator plans to study the mechanisms underlying the role of B-cells in NOD diabetogenesis. Thus, specific aim 1 will be focused on elucidating the contribution of MHC class I and class II mediated antigen presentation by B-cells to NOD diabetogenesis.
In specific aim 2, studies are proposed to assess the contribution of the autoreactive subset of B- cells to NOD diabetogenesis by skewing the NOD B-cell repertoire away from diabetes associated Ig specificities.
Specific aim 3 will address the importance of C3-mediated B-cell activation and antigen uptake in the development of anti-islet autoantibodies and diabetogenesis in NOD mice.
In specific aim 4, the studies to be pursued aimed at elucidating the regulation of self-reactive B-cells in the NOD microenvironment. Insights into the mechanisms by which B-cells contribute to the etiology of autoimmune diabetes will provide the basis for the design of novel strategies for the prevention of IDDM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054215-04
Application #
6381183
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
1998-08-05
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$187,572
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhao, G; Moore, D J; Lee, K M et al. (2010) An unexpected counter-regulatory role of IL-10 in B-lymphocyte-mediated transplantation tolerance. Am J Transplant 10:796-801
Huang, Xiaolun; Moore, Daniel J; Mohiuddin, Mohammad et al. (2008) Inhibition of ICAM-1/LFA-1 interactions prevents B-cell-dependent anti-CD45RB-induced transplantation tolerance. Transplantation 85:675-80
Moore, Daniel J; Noorchashm, Hooman; Lin, Tina H et al. (2005) NOD B-cells are insufficient to incite T-cell-mediated anti-islet autoimmunity. Diabetes 54:2019-25
Moore, Daniel J; Huang, Xiaolun; Lee 4th, Major K et al. (2004) Resistance to anti-CD45RB-induced tolerance in NOD mice: mechanisms involved. Transpl Int 17:261-9
Reed, Amy J; Noorchashm, Hooman; Rostami, Susan Y et al. (2003) Alloreactive CD4 T cell activation in vivo: an autonomous function of the indirect pathway of alloantigen presentation. J Immunol 171:6502-9
Greeley, Siri Atma W; Katsumata, Makoto; Yu, Liping et al. (2002) Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 8:399-402
Greeley, S A; Moore, D J; Noorchashm, H et al. (2001) Impaired activation of islet-reactive CD4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice. J Immunol 167:4351-7
Larson, R A; Naji, M; Lombardi, J V et al. (2000) Adenoviral-mediated uteroglobin gene transfer inhibits neointimal hyperplasia after balloon injury in the rat carotid artery. J Vasc Surg 32:1111-7
Noorchashm, H; Lieu, Y K; Noorchashm, N et al. (1999) I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice. J Immunol 163:743-50