A5001121007- Diabetes and associated disorders
- Pancreatic function and diabetes
- Diabetes Management and Research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Chronic Lymphocytic Leukemia Research
- Monoclonal and Polyclonal Antibodies Research
- Metabolism, Diabetes, and Cancer
- Platelet Disorders and Treatments
- Cell Adhesion Molecules Research
- Cannabis and Cannabinoid Research
- Rheumatoid Arthritis Research and Therapies
- Immunotherapy and Immune Responses
- Autoimmune Bullous Skin Diseases
- Birth, Development, and Health
- Pancreatitis Pathology and Treatment
- Blood properties and coagulation
- Genetics and Neurodevelopmental Disorders
- Diabetes Treatment and Management
- Transgenic Plants and Applications
University of Colorado Denver
2012-2025
University of Colorado Anschutz Medical Campus
2011-2023
National Jewish Health
2008-2015
University of British Columbia
2010
T cells target peptide combos One of the enduring mysteries autoimmunity is identity specific proteins targeted by autoimmune cells. Delong et al. used mass spectrometry to elucidate targets isolated from a mouse model type 1 diabetes. hybrid peptides formed covalent linking derived pro-insulin other found in pancreatic beta islets two individuals with diabetes also recognized such peptides, suggesting that they may play an important role driving disease. Science , this issue p. 711
Islet transplantation is a promising treatment for diabetes but long-term success limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote apoptosis and rapid formation occurs in transplanted islets. Porcine islets are an attractive alternative source as they demonstrate survival. We compared capacity human porcine to form explanation differences Human were into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was...
Chromogranin A (ChgA) has been identified as the antigen target for three NOD-derived, diabetogenic CD4 T-cell clones, including well-known BDC-2.5. These clones respond weakly to peptide WE14, a naturally occurring proteolytic cleavage product from ChgA. We show here that WE14 can be converted into highly antigenic epitope through treatment with enzyme transglutaminase (TGase). The responses of NOD-derived each different receptors (TCRs), and T cells BDC-2.5 TCR transgenic mice are...
We recently established that hybrid insulin peptides (HIPs) are present in human islets and T cells reactive to HIPs found the residual of organ donors with type 1 diabetes (T1D). Here, we investigate whether HIP-reactive indicative ongoing autoimmunity patients T1D. used interferon-γ enzyme-linked immune absorbent spot analyses on peripheral blood mononuclear (PBMCs) determine new-onset T1D or control subjects displayed T-cell reactivity a panel 16 HIPs. observed nearly one-half responded...
We recently established that hybrid insulin peptides (HIPs), formed in islet β-cells by fusion of C-peptide fragments to chromogranin A or amyloid polypeptide, are ligands for diabetogenic CD4 T-cell clones. The goal this study was investigate whether HIP-reactive T cells were indicative ongoing autoimmunity. MHC class II tetramers used the presence, phenotype, and function insulin-reactive NOD mice. Insulin-reactive encounter their antigen early disease, but they express FoxP3 therefore may...
Abstract CD4 T cells play a critical role in promoting the development of autoimmunity type 1 diabetes. The diabetogenic cell clone BDC-2.5, originally isolated from NOD mouse, has been widely used to study contribution autoreactive and relevant Ags autoimmune Recent work our laboratory shown that Ag for BDC-2.5 is hybrid insulin peptide (2.5HIP) consisting an C-peptide fragment fused chromogranin A (ChgA) endogenous 2.5HIP-reactive are major contributors pathology mice. objective this was...
Hybrid insulin peptides (HIPs) form in pancreatic β-cells through the formation of peptide bonds between proinsulin fragments and other peptides. HIPs have been identified islets by mass spectrometry are targeted CD4 T cells patients with type 1 diabetes (T1D) as well pathogenic T-cell clones nonobese diabetic (NOD) mice. The mechanism HIP is currently poorly understood; however, it established that proteases can drive new a side reaction during bond hydrolysis. Here, we used proteomic...
T cells isolated from the pancreatic infiltrates of nonobese diabetic mice have been shown to recognize epitopes formed by covalent cross-linking proinsulin and secretory granule peptides. Formation such hybrid insulin peptides (HIPs) was confirmed through mass spectrometry, responses HIPs were observed among islet-infiltrating organ donors in peripheral blood individuals with type 1 diabetes (T1D). However, questions remain about prevalence HIP-specific humans, sequences they recognize,...
Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in cell-mediated beta-cell destruction. We have shown HIPs form human islets between fragments of the C-peptide and cleavage products secretory granule proteins. To identify cell specificities contributing T1D pathogenesis, we tested reactivity from patients or healthy control using IFN-γ ELISPOT assay against...
<p dir="ltr">Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in cell-mediated beta-cell destruction. We have shown HIPs form human islets between fragments of the C-peptide and cleavage products secretory granule proteins. To identify cell specificities contributing T1D pathogenesis, we tested reactivity from patients or healthy control using IFN-g...
<p dir="ltr">Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in cell-mediated beta-cell destruction. We have shown HIPs form human islets between fragments of the C-peptide and cleavage products secretory granule proteins. To identify cell specificities contributing T1D pathogenesis, we tested reactivity from patients or healthy control using IFN-g...
OBJECTIVE To investigate autoantigens in β-cells, we have used a panel of pathogenic T-cell clones that were derived from the NOD mouse. Our particular focus this study was on identification target antigen for highly diabetogenic clone BDC-5.2.9. RESEARCH DESIGN AND METHODS purify β-cell antigens, applied sequential size exclusion chromatography and reverse-phase high-performance liquid to membrane preparations tumors. The presence monitored by measuring interferon-γ production BDC-5.2.9...
T cells reactive to β cell Ags are critical players in the development of autoimmune type 1 diabetes. Using a panel diabetogenic CD4 clones derived from NOD mouse, we recently identified secretory granule protein, chromogranin A (ChgA), as new autoantigen ChgA pathogenic and rapidly transfer diabetes into young recipients. We report this article that NOD.ChgA(-/-) mice do not develop show little evidence autoimmunity pancreatic islets. tetramer analysis, demonstrate ChgA-reactive present...
<p dir="ltr">Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in cell-mediated beta-cell destruction. We have shown HIPs form human islets between fragments of the C-peptide and cleavage products secretory granule proteins. To identify cell specificities contributing T1D pathogenesis, we tested reactivity from patients or healthy control using IFN-g...
Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule are detectable within murine and human islets. The 2.5HIP (C-peptide–chromogranin A [CgA] HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in nonobese diabetic mouse. However, relevance this epitope disease currently unclear. recent study probed T-cell reactivity toward HIPs patients with type 1 diabetes, documenting responses one-third isolating several...
Abstract We previously reported a peptide KS20 from islet amyloid polypeptide (IAPP) to be the target Ag for highly diabetogenic CD4 T cell clone BDC-5.2.9. To track IAPP-reactive cells in NOD mice and determine how they contribute pathogenesis of type 1 diabetes, we designed new I-Ag7 tetramer with high affinity BDC-5.2.9 that contains KS20. found significant numbers tetramer+ can detected pancreas prediabetic diabetic mice. verify pathogenicity cells, sorted cloned them uncloned lines...
Hybrid Insulin Peptides (HIPs), which consist of insulin fragments fused to other peptides from β-cell secretory granule proteins, are CD4 T cell autoantigens in type 1 diabetes (T1D). We have studied HIPs and HIP-reactive cells extensively the context non-obese diabetic (NOD) mouse model autoimmune shown that specific for major contributors disease pathogenesis. Additionally, human context, can be found islets peripheral blood T1D patients. Here, we performed an in-depth characterization...
Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches address the limited clinical efficacy ASIT. Soluble antigen arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to hyaluronic acid backbone using either hydrolysable linkers (hSAgAs) stable click chemistry (cSAgAs). They were evaluated ability block spontaneous development...
The induction of antigen (Ag)-specific tolerance and replacement islet β-cells are major ongoing goals for the treatment type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is critical autoantigen diabetogenic CD4+ T cells in NOD mouse model. In this study, we investigated whether Ag-specific using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic mice from disease recurrence upon syngeneic transplantation. Islet graft survival was...
Insulin is considered to be a key antigenic target of T cells in Type 1 Diabetes (T1D) and autoimmune diabetes the NOD mouse with particular focus on B-chain amino acid sequence B:9-23 as primary epitope. Our lab previously discovered that hybrid insulin peptides (HIPs), comprised C-peptide fragments fused other β-cell granule peptides, are ligands for several pathogenic CD4 cell clones derived from mice autoreactive T1D patients. A subset our panel react but only at high concentrations...