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1.
J Immunol ; 194(10): 4804-13, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25862815

ABSTRACT

Previous studies in mouse models of autoimmune diabetes and encephalomyelitis have indicated that the selective delivery of self-antigen to the endocytic receptor DEC205 on steady-state dendritic cells (DCs) may represent a suitable approach to induce Ag-specific immune tolerance. In this study, we aimed to examine whether DEC205(+) DC targeting of a single immunodominant peptide derived from human cartilage proteoglycan (PG) can promote immune tolerance in PG-induced arthritis (PGIA). Besides disease induction by immunization with whole PG protein with a high degree of antigenic complexity, PGIA substantially differs from previously studied autoimmune models not only in the target tissue of autoimmune destruction but also in the nature of pathogenic immune effector cells. Our results show that DEC205(+) DC targeting of the PG peptide 70-84 is sufficient to efficiently protect against PGIA development. Complementary mechanistic studies support a model in which DEC205(+) DC targeting leads to insufficient germinal center B cell support by PG-specific follicular helper T cells. Consequently, impaired germinal center formation results in lower Ab titers, severely compromising the development of PGIA. Overall, this study further corroborates the potential of prospective tolerogenic DEC205(+) DC vaccination to interfere with autoimmune diseases, such as rheumatoid arthritis.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Dendritic Cells/immunology , Immune Tolerance/immunology , Vaccines/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Mice , Mice, Inbred BALB C , Mice, Transgenic
2.
PLoS One ; 9(2): e88869, 2014.
Article in English | MEDLINE | ID: mdl-24551182

ABSTRACT

Previous studies have suggested that murine peritoneal cavity-derived B-1a cells possess similarities with described regulatory B cell subsets. The aim of the current study was to examine the potential immunoregulatory function of peritoneal cavity-derived B(-1a) cells. In vitro activation of peritoneal cavity-derived B- and B-1a cells shows that activation of these B cells with anti-CD40 and LPS induces these cells to secrete more IL-10, IL-6 and IgM as compared to splenic B cells. In a suppression assay, CD40/TLR4-activated peritoneal cavity B cells possess regulatory B cell functions as they inhibit the capacity of CD4(+) T cells to produce both tumor necrosis factor-α and interferon-γ. Splenic B cells did not show this, whereas non-activated peritoneal cavity B cells augmented the capacity of CD4(+) T cells to produce tumor necrosis factor-α, while the ability to produce interferon-γ was not altered. The current paper compares splenic B cells to peritoneal cavity B(-1a) cells in an in vitro activation- and an suppression-assay and concludes that peritoneal cavity B(-1a) cells possess properties that appear similar to splenic autoimmune-suppressive regulatory B cell subsets described in the literature.


Subject(s)
B-Lymphocytes, Regulatory/immunology , CD4-Positive T-Lymphocytes/immunology , Immunity, Innate , Peritoneal Cavity/cytology , Animals , Antibodies/pharmacology , B-Lymphocytes, Regulatory/cytology , B-Lymphocytes, Regulatory/drug effects , CD4-Positive T-Lymphocytes/cytology , CD40 Antigens/immunology , Coculture Techniques , Female , Immunoglobulin M/immunology , Immunoglobulin M/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Spleen/cytology , Spleen/immunology , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism
3.
Int Immunopharmacol ; 17(4): 1075-83, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24177275

ABSTRACT

Rheumatoid arthritis (RA) is a chronic T-cell mediated autoimmune disease that affects primarily the joints. The induction of immune tolerance through antigen-specific therapies for the blockade of pathogenic CD4+ T cells constitutes a current focus of research. In this focus it is attempted to simultaneously activate multiple regulatory mechanisms, such as: apoptosis and regulatory T cells (Tregs). APL-1 is an altered peptide ligand derived from a novel CD4+ T-cell epitope of human heat-shock protein of 60kDa, an autoantigen involved in the pathogenesis of RA. Previously, we have reported that APL-1 induces CD4+ CD25(high)Foxp3+ Tregs in several systems. Here, we investigated the ability of APL-1 in inducing apoptosis in PBMCs from RA patients, who were classified as active or inactive according to their DAS28 score. APL-1 decreased the viability of PBMCs from active but not from inactive patients. DNA fragmentation assays and typical morphological features clearly demonstrated that APL-1 induced apoptosis in these cells. Activated CD4+ CD25+ T cells but not resting CD4+ CD25- T cells were identified as targets of APL-1. Furthermore, CD4+ T-cell responses to APL-1 were found to be dependent on antigen presentation via the HLA-DR molecule. Thus, APL-1 is a regulatory CD4+ T cell epitope which might modulate inflammatory immune responses in PBMCs from RA patients by inducing CD4+ CD25(high)Foxp3+ Tregs and apoptosis in activated CD4+ T cells. These results support further investigation of this candidate drug for the treatment of RA.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Rheumatoid/immunology , CD4-Positive T-Lymphocytes/drug effects , Chaperonin 60/pharmacology , Peptide Fragments/pharmacology , Peptides/pharmacology , Adult , Aged , Apoptosis/drug effects , CD4-Positive T-Lymphocytes/immunology , Cell Line , Cell Survival/drug effects , Chaperonin 60/immunology , DNA Fragmentation/drug effects , Female , Humans , Interleukin-2 Receptor alpha Subunit/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/ultrastructure , Ligands , Male , Middle Aged , Mitochondrial Proteins/immunology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
4.
Eur J Immunol ; 43(9): 2317-26, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23719868

ABSTRACT

Innate-like murine B-1a cells are well known for their ability to secrete natural IgM. Their non-Ab mediated functions, including Ag presentation to CD4(+) T cells, are less well explored. Using combined adoptive transfer experiments with peptide-pulsed peritoneal cavity (PerC)-derived B-1a cells and CFSE-labeled T cells, we show that B-1a cells present Ag to CD4(+) T cells from the periphery in vivo. In vitro characterization, using co-cultures in which B-1a or splenic B cells presented whole OVA protein to OVA-specific Tg T cells, shows that B-1a cells differentially promote intracellular cytokine-expressing T cells. PerC-derived B-1a cells increase the percentage of IL-10-producing T cells along with IL-4- and IFN-γ-producing CD4(+) T cells. These data suggest that B cells in the PerC have the potential to influence peripheral immune responses without the necessity to migrate out of this location. This, to our knowledge previously undescribed, immuno-logical pathway potentially plays a role in the presentation of gut microbiota-derived Ags to peripheral T cells.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Lymphocyte Activation , Peritoneal Cavity/cytology , Adoptive Transfer , Animals , Antigen-Presenting Cells/immunology , Cells, Cultured , Coculture Techniques , Interferon-gamma/biosynthesis , Interleukin-10/biosynthesis , Interleukin-4/biosynthesis , Mice , Mice, Inbred BALB C , Ovalbumin/immunology
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