The autoimmune disease process underlying insulin dependent diabetes (IDD) relies upon interactions between genetic susceptibility genes located both inside and outside of the major histocompatibility complex (MHC) and multiple components of the immune system (i.e., antigen presenting cells, T-cells). Whereas previous studies have demonstrated that individuals with or at increased-risk for IDD (i.e., islet cell autoantibody positive relatives) display a number of immune abnormalities, the contribution of IDD susceptibility genes to these processes are poorly understood. The goal of this program project is to examine the immune system of individuals at varying risks for IDD in order to elucidate the mechanisms by which IDD susceptibility genes interact with antigen presenting cells and T-cells to engender the autoimmune destruction of pancreatic beta cells. This program will examine this question through three separate projects: Project 1 - The Roles of CTLA-4 and CD28 in IDDM Pathogenesis; Project 2 - PGS2 in the Pathogenesis of IDD in Humans and NOD Mice; and Project 3 - Immune Function and Genetic Susceptibility for IDD. Project I is designed to characterize the recently identified IDDM12 gene using a combination of genetic and functional analyses. This project will further define the genomic interval for IDDM12, and evaluate CTLA4 & CD28 as candidate genes for this disease susceptibility interval. With preliminary evidence that NOD mice and humans at increased-risk for IDD display abnormally high-levels of prostaglandin synthase-2 (PGS-2), project 2 will seek to identify a role for this molecule in the pathogenesis of IDD. Specifically, this project will define a genetic basis for the aberrant PGS-2 expression, and identify the effects of PGS-2 expression on monocyte/macrophage function, T-cell activation, and peripheral tolerance mechanisms. Project 3 will prospectively monitor a number of cellular immune activities (i.e., blastogenesis/cytokine production to beta cell antigens, expression of immunoregulatory molecules, class Il peptide binding of beta cell autoantigens) in individuals at very high- risk, low-risk, or extremely low-risk for IDD. Additional studies will monitor these immunological parameters in persons divergent in non-MHC linked susceptibility genes (i.e., IDDM2, IDDM12). These projects will be supported by three core facilities; A-Administration; B-Mouse Facility; C-Laboratory). The successful completion of this study will be beneficial to improve our understanding of events critical to the natural history of progression to IDD, identify genetic/immunologic screening tools for the disease, and develop selective immunotherapies for the prevention of IDD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042288-03
Application #
2887648
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Collier, Elaine S
Project Start
1997-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Perry, Daniel J; Wasserfall, Clive H; Oram, Richard A et al. (2018) Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling. Sci Rep 8:4529
Chen, Yi-Guang; Mathews, Clayton E; Driver, John P (2018) The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Front Endocrinol (Lausanne) 9:51
Kusmartseva, Irina; Beery, Maria; Philips, Tiffany et al. (2018) Hospital time prior to death and pancreas histopathology: implications for future studies. Diabetologia 61:954-958
Hu, Ronghua; Xia, Chang-Qing; Butfiloski, Edward et al. (2018) Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: Implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection. Clin Immunol 195:139-148
Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive et al. (2018) Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles. Diabetes 67:697-703
Whitener, Robert L; Gallo Knight, Lisa; Li, Jianwei et al. (2017) The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice. J Immunol 199:3991-4000
Wang, Qiming; Racine, Jeremy J; Ratiu, Jeremy J et al. (2017) Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy. J Immunol 199:3757-3770
Yeh, Wen-I; Seay, Howard R; Newby, Brittney et al. (2017) Avidity and Bystander Suppressive Capacity of Human Regulatory T Cells Expressing De Novo Autoreactive T-Cell Receptors in Type 1 Diabetes. Front Immunol 8:1313
Campbell-Thompson, Martha L; Atkinson, Mark A; Butler, Alexandra E et al. (2017) Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Diabetologia 60:753-755
Wallet, Mark A; Santostefano, Katherine E; Terada, Naohiro et al. (2017) Isogenic Cellular Systems Model the Impact of Genetic Risk Variants in the Pathogenesis of Type 1 Diabetes. Front Endocrinol (Lausanne) 8:276

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