The autoimmune disease process underlying type 1 diabetes (type 1 DM) 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 cell (APC), T-cells]. Whereas previous studies have demonstrated that individuals with or at increased-risk of type 1 DM (e.g., autoantibody positive relatives) display a number of immunological abnormalities, the contribution of specific genes to this process as well as an informative description of the interactions between specialized immunoregulatory cell populations remains unclear. Our goal in seeking renewal of this program project grant (PPG) is to continue to elucidate the mechanisms by which type I DM susceptibility genes interact with APC (B-cells, dendritic cells, macrophage/monocytes) and cellular immune system components (T-cells, NK T cells) to engender the autoimmune destruction of pancreatic beta cells. This PPG will examine this important issue through three separate but highly interactive projects: B- Lymphocyte Subsets in Type I Diabetes; PGS2 in the Pathogenesis of Type I DM; Cellular Immunoregulation by DC and Diabetes Progression. The first project will examine the molecular and cellular mechanisms underlying the recent observations revealing a critical role for B-lymphocytes in the formation of type 1 DM and insulitis in NOD mice. With convincing data that NOD mice and humans at increased-risk for type 1 DM display abnormally high levels of prostaglandin synthase- 2 (PGS-2), the second Project will seek to identify a role for this molecule in the pathogenesis of the disorder. The third Project will prospectively monitor a number of cellular immune activities (i.e., blastogenesis/cytokine production to beta cell antigens, analyze DC subsets and APC function, frequency of CD1d-restricted T cells( recently ascribed as being critical to diabetes susceptibility and progression to disease. Both Projects 2 and 3 will involve examination of extremely valuable study populations with type 1 DM or at various levels of risk for the disease including those participating in diabetes prevention trials and studies involving perspective assessment of autoimmunity in newborns. These Projects will be supported by three Core facilities: Mouse Facility; Laboratory. The successful completion of these PPG studies will be beneficial to improving our understanding of events critical to the natural history of progression to type 1 DM, identify genetic/immunologic screening tools for the disease, and potentially, to uncover selective immunotherapies capable of preventing the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042288-06
Application #
6532738
Study Section
Special Emphasis Panel (ZAI1-NN-I (S3))
Program Officer
Ridge, John P
Project Start
1997-09-30
Project End
2006-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
6
Fiscal Year
2002
Total Cost
$936,569
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
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Delitto, Daniel; Delitto, Andrea E; DiVita, Bayli B et al. (2017) Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment. Cancer Res 77:672-683
Posgai, Amanda L; Wasserfall, Clive H; Kwon, Kwang-Chul et al. (2017) Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice. Sci Rep 7:42372
Sebastiani, Guido; Ventriglia, Giuliana; Stabilini, Angela et al. (2017) Regulatory T-cells from pancreatic lymphnodes of patients with type-1 diabetes express increased levels of microRNA miR-125a-5p that limits CCR2 expression. Sci Rep 7:6897
O'Kell, Allison L; Wasserfall, Clive; Catchpole, Brian et al. (2017) Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked? Diabetes 66:1443-1452

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