Human type 1 diabetes (T1D) is characterized by the specific immune-mediated destruction of insulin- producing pancreatic beta cells. Importantly, earlier studies demonstrated that immune memory to beta cell antigens plays a significant role in their destruction, which constitutes a major obstacle for long-term acceptance of islet cell grafts (1-3). There is now consensus that CD8 T cells constitute the principal T cell type in insulitis in recent-onset patients (4). Such CD8 T cells are potentially very harmful, since they have been shown to readily kill human beta cells in vivo, if enough MHC class I is upregulated on their surface (5). However, not much is known about the overall CD8 specificities and frequencies present in islets and the cause for their entry and activation. Possible targets are known autoantigens derived from beta cells such as insulin, IGRP, IA-2 and GAD (see Table 1 for abbreviations) and cellular matrix proteins, which could become presented when beta cells are destroyed but also viral proteins for example enteroviral determinants. The overall objective of this proposal is therefore to reveal the specificity of CD8 T lymphocytes that are found in human islets and address whether viral infections may play a role in this scenario. [In parallel studies, we aim to confirm our preliminary data showing that islet infiltration may persist long beyond clinical diagnosis and in such cases follows a continuous course both quantitatively and qualitatively. The latter finding would have broad implications on the feasibility of experimental tolerization therapies in longstanding patients.] Our first goal is to systematically detect autoreactive CD8 T cells within human islets and correlate their numbers and activation status with the local histopathology of the islet. In situ tetramer staining of freshly frozen human pancreata and pancreatic lymph nodes now available through the unique nPOD organ repository will be used. In addition, humanized HLA A2 expressing transgenic mice will be utilized to map responses to novel cellular matrix (self) epitopes which will then be validated on human tissues. Our second goal is to search for [CVB]-specific T cells within islets and address the important question, whether viral infection makes islets more accessible for autoreactive T cell or vice versa. To this purpose human sections from pancreata of diabetic patients will be probed with [CVB-specific] tetramers and viral nucleic acids will be detected in collaboration with Heikki Hyoty and Stephen Tracy. In addition, diabetes- prone HLA-A2 humanized mice and fluorescently labeled Coxsackie B virus strains will be used to address the fundamental 'chicken-egg' question, whether viral infections are more important to condition islets for autoreactive lymphocyte entry and destruction, or, conversely, whether autoreactive attacks make islets more accessible for enteroviral infections.

Public Health Relevance

We wish to systematically investigate the specificity of the immune cells that destroy insulin-producing beta cells in pancreas tissue obtained from patients with type 1 diabetes. Additionally, we will evaluate the potential role of enteroviruses in type 1 diabetes development in both patients and mouse models. This research will expand our knowledge on how the disease is triggered in susceptible individuals and on how we may therapeutically target these cells in order to restore tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092453-05
Application #
8828063
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2011-05-02
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Rodriguez-Calvo, Teresa; Zapardiel-Gonzalo, Jose; Amirian, Natalie et al. (2017) Increase in Pancreatic Proinsulin and Preservation of ?-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 66:1334-1345
Richardson, Sarah J; Rodriguez-Calvo, Teresa; Gerling, Ivan C et al. (2016) Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59:2448-2458
Rodriguez-Calvo, Teresa; Suwandi, Jessica S; Amirian, Natalie et al. (2015) Heterogeneity and Lobularity of Pancreatic Pathology in Type 1 Diabetes during the Prediabetic Phase. J Histochem Cytochem 63:626-36
Coppieters, Ken T; von Herrath, Matthias G (2014) The type 1 diabetes signature: hardwired to trigger inflammation? Diabetes 63:3581-3
Rodriguez-Calvo, Teresa; Ekwall, Olov; Amirian, Natalie et al. (2014) Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 63:3880-90
Coppieters, Ken T; Harrison, Leonard C; von Herrath, Matthias G (2013) Trials in type 1 diabetes: Antigen-specific therapies. Clin Immunol 149:345-55
Coppieters, Ken T; Wiberg, Anna; von Herrath, Matthias G (2012) Viral infections and molecular mimicry in type 1 diabetes. APMIS 120:941-9
Coppieters, Ken T; von Herrath, Matthias G (2012) Motifs for a deadly encounter. Nat Immunol 13:205-6
Coppieters, Ken T; Boettler, Tobias; von Herrath, Matthias (2012) Virus infections in type 1 diabetes. Cold Spring Harb Perspect Med 2:a007682
Coppieters, Ken T; Sehested Hansen, Birgit; von Herrath, Matthias G (2012) Clinical potential of antigen-specific therapies in type 1 diabetes. Rev Diabet Stud 9:328-37

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