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1.
J Immunol ; 204(7): 1787-1797, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32111734

ABSTRACT

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4+ mimotope (BDC2.5mim) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3+ and Foxp3- PD1+ CD73+ ICOS+ IL-10+ peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5mim/calcitriol liposome administration, adoptive transfer of CD4+ T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5mim/calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit-related protein-specific CD8+ T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4+ peptide, BDC2.5mim, and calcitriol induce ChgA-specific CD4+ T cells that regulate CD4+ and CD8+ self-antigen specificities and autoimmune diabetes in NOD mice.


Subject(s)
Autoantigens/immunology , Autoimmune Diseases/immunology , Autoimmunity/immunology , Diabetes Mellitus, Type 1/immunology , Islets of Langerhans/immunology , Liposomes/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmune Diseases/therapy , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Diabetes Mellitus, Type 1/therapy , Female , Immune Tolerance/immunology , Immunotherapy/methods , Mice , Mice, Inbred NOD , Mice, SCID , Peptides/immunology
2.
Int J Mol Sci ; 19(10)2018 Oct 07.
Article in English | MEDLINE | ID: mdl-30301262

ABSTRACT

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis.


Subject(s)
Biomarkers, Tumor/standards , Cyclin-Dependent Kinase Inhibitor p18/genetics , Lung Neoplasms/genetics , Mesothelioma/genetics , Primary Cell Culture/standards , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/genetics , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Cell Line, Tumor , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16 , Gene Deletion , Humans , Lung Neoplasms/pathology , Male , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Primary Cell Culture/methods
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