Project Abstracts - CMAI

Maki Nakayama, MD, PhD, co-Investigator, University of Colorado Denver
Peter Gottlieb, MD, co-Investigator, University of Colorado Denver
Aaron Michels, MD, co-Investigator, University of Colorado Denver
John Kappler, PhD, co-Investigator, National Jewish Medical and Research Center

Start Date: September 30, 2014
End Date: June 30, 2019

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Abstract

Most evidence indicates that Type 1 Diabetes (T1D) results from T cell-dependent destruction of insulin producing beta cells within pancreatic islets. A major developmental focus of the Human Islet Research Network and Consortium on Modeling Autoimmune Interactions (HIRN-CMAI) is to generate ‘humanized’ mouse models suitable for studying human autoreactivity in vivo.  This is a challenging and ongoing goal of many research groups, including those at our own Center.  We perceive that one key current limitation of such animal models is the ambiguity in defining the specificity and function of defined human autoreactive T cell receptors (TCR). Over several years, a number of investigators have isolated a variety of candidate human autoreactive T cell lines and clones derived from T1D subjects.  However, the direct role of these differing self-antigen specific T cells in mediating islet beta cell injury remains poorly understood. Therefore, our group proposes to develop a comprehensive program to introduce a series of human autoreactive TCRs into suitable human HLA mouse models to interrogate autoreactivity in vivo.  To this end, we have developed collaborations from several investigators world wide to amass a number of islet-reactive T cells from which to harvest human autoreactive TCRs genetic sequences.  Our goal is to translate these candidate human TCRs into reproducible animal models by merging three major areas of expertise at our Institution:  1) Expertise in studying human autoreactivity in T1D, 2) Expertise in TCR structure and function and the introduction of TCR gene sequences into animals using ‘retrogenic’ technology, and 3) Extensive experience in small animal modeling to study T cell reactivity to both native and transplanted islets in vivo.

Publications

• Human islet T cells are highly reactive to preproinsulin in type 1 diabetes
• Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors
• Diverse Routes of Allograft Tolerance Disruption by Memory T Cells
• Multiplex T Cell Stimulation Assay Utilizing a T Cell Activation Reporter-Based Detection System
• Determining Antigen Specificity of Human Islet Infiltrating T Cells in Type 1 Diabetes
• CD4 T Cells Reactive to Hybrid Insulin Peptides Are Indicators of Disease Activity in the NOD Mouse
• Development of T cell lines sensitive to antigen stimulation
• Learning From Past Failures of Oral Insulin Trials
• β Cell replacement: improving on the design
• Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes
• Revealing the specificity of regulatory T cells in murine autoimmune diabetes
• Simultaneous Recognition of Allogeneic MHC and Cognate Autoantigen by Autoreactive T Cells in Transplant Rejection
• The somatically generated portion of T cell receptor CDR3α contributes to the MHC allele specificity of the T cell receptor
• Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”
• Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes
• Differential Impact of Chronic Hyperglycemia on Humoral Versus Cellular Primary Alloimmunity
• PAX6 maintains β cell identity by repressing genes of alternative islet cell types