Avoidance of autoimmunity appears to rely on a carefully orchestrated series of activities involving an appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems. When this process fails, a variety of autoimmune disorders can arise;including type 1 diabetes where insulin producing pancreatic p cells are destroyed. Adaptive CD4'^ T helper (TH) cells orchestrate the nature and duration of immune responses through distinct properties of lineage-specific cell subsets (e.g., THI, TH17, regulatory T cells (Treg), etc.). The overall objective of Project 2 is to characterize the interplay between antigen presenting cells (APC) and TH subsets, identify their mechanistic contribution to the pathogenesis of TID, evaluate the potential of these cells to serve as markers for autoimmune disease activity. In addition, a major emphasis will be given to evaluate the contributions of specific candidate genotypes previously identified in genome wide association studies (GWAS), for their contribution to immune regulation (Project 2 - ILISRAP, TLRS;Project 1 - IFIHI). This project emanates from literature suggesting that patients with TID exhibit a remarkable loss of immunoregulation whose cellular contributors include proinflammatory APC, unstable and functionally defective Treg, and persistent T effector cells (Teff) that are refractory to regulation. Project 2 will test the hypothesis that in TID, CD4^ T cells are functionally defective and that the molecular &cellular basis for this defect resides in interactions between the innate and adaptive immune response (including dendritic cells, natural killer (NK) cells, & iNKT cells) as well as the balance between Teff and Treg subsets. We believe Project 2 finds marked innovation through the integrative approach afforded by the POI mechanism, the use of novel methodologies to isolate the cellular source of defects, the study of genetic loci underrepresented in TID research and quite importantly, our ability to explore lymphoid and pancreatic tissues and cells from the nPOD program.

Public Health Relevance

Patients with TID, as well as those at risk for developing the disease, would benefit from this research in it's provision of an improved understanding of how and why the disorder develops. In addition. Project 2 holds the promise of providing improved biomarkers that better identify risk for developing TID, as well as novel therapeutics capable of preventing and/or reversing the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042288-16
Application #
8660583
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
16
Fiscal Year
2014
Total Cost
$433,149
Indirect Cost
$144,062
Name
University of Florida
Department
Type
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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