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1.
Front Immunol ; 12: 763379, 2021.
Article in English | MEDLINE | ID: mdl-34691085

ABSTRACT

Every immune response has accelerators and brakes. Depending on the pathogen or injury, monocytes can play either role, promoting or resolving immunity. Poly I:C, a potent TLR3 ligand, licenses cross-presenting dendritic cells (DC1) to accelerate a robust cytotoxic T cells response against a foreign antigen. Poly I:C thus has promise as an adjuvant in cancer immunotherapy and viral subunit vaccines. Like DC1s, monocytes are also abundant in the LNs. They may act as either immune accelerators or brakes, depending on the inflammatory mediator they encounter. However, little is known about their contribution to adaptive immunity in the context of antigen and Poly I:C. Using monocyte-deficient and chimeric mice, we demonstrate that LN monocytes indirectly dampen a Poly I:C induced antigen-specific cytotoxic T cell response, exerting a "braking" function. This effect is mediated by IL-10 production and induction of suppressor CD4+ T cells. In a metastatic melanoma model, we show that a triple-combination prophylactic treatment consisting of anti-IL-10, tumor peptides and Poly I:C works because removing IL-10 counteracts the monocytic brake, resulting in significantly fewer tumors compared to mice treated with tumor peptides and Poly I:C alone. Finally, in human LN tissue, we observed that monocytes (unlike DCs) express high levels of IL-10, suggesting that anti-IL-10 may be an important addition to treatments. Overall, our data demonstrates that LN monocytes regulate the induction of a robust DC1-mediated immune response. Neutralization of either IL-10 or monocytes can augment Poly I:C-based treatments and enhance T cell cytotoxicity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Interleukin-10/physiology , Lymph Nodes/immunology , Monocytes/physiology , Poly I-C/pharmacology , T-Lymphocytes, Cytotoxic/drug effects , Animals , Humans , Interleukin-10/antagonists & inhibitors , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Receptors, CCR2/physiology , T-Lymphocytes, Cytotoxic/immunology
2.
Clin Exp Med ; 14(4): 361-73, 2014 Nov.
Article in English | MEDLINE | ID: mdl-23996469

ABSTRACT

Immunoglobulins are glycoproteins produced by the cells of the immune system. Their primary function is to protect the body from pathogenic infection. Moreover, a concentrated polyclonal mixture of immunoglobulin G (IgG), the so-called intravenous IgG (IVIG), has been used to treat various chronic and systemic disorders of the immune system. Studies on the effects of IVIG in autoimmune disease models have revealed that IgG Fc fragments confer protection against various autoimmune diseases. The identification of this IgG Fc immunomodulatory component is important for the development of IVIG substitutes. The focus of this review is to introduce one of the Fc regulatory entities and to provide a summary of the current knowledge of the putative general mechanisms underlying IVIG activity in vivo on the basis of these Fc fragments. We also address the recent insights into several approaches for the development of IVIG substitutes.


Subject(s)
Immunoglobulin Fc Fragments/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Immunosuppression Therapy/methods , Immunosuppressive Agents/therapeutic use , Humans , Immunoglobulin Fc Fragments/pharmacology , Immunoglobulins, Intravenous/pharmacology , Immunosuppressive Agents/pharmacology
3.
Hybridoma (Larchmt) ; 30(2): 109-16, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21529282

ABSTRACT

Dextran was used to explore a novel method of enhancing an immune response against T-cell independent type 2 (TI-2) polysaccharide antigens, because of its suitability as a model for the immunogenecity of many TI-2 polysaccharide antigens and its high affinity to SIGN-R1. Here we showed that the primary immune response of IgM, IgG3, and IgG2b was enhanced by dextran in SIGN-R1 knock-out (KO) mice, further evoking the induction of a secondary immune response to IgG2b in parallel. On the other hand, an immune response of IgG1 and IgG2b against T-cell dependent (TD) antigen was strongly enhanced by the administration of ovalbumin (OVA) in SIGN-R1 KO mice. These results indicate that SIGN-R1 is critical in the regulation of immune responses. Therefore, our study suggests that inhibition of TI-2 polysaccharide antigen uptake in SIGN-R1(+) macrophages contributes to the development of novel vaccination strategies against TI-2 polysaccharide antigens.


Subject(s)
Antigens, T-Independent/immunology , Cell Adhesion Molecules/immunology , Dextrans/pharmacology , Fluorescein-5-isothiocyanate/analogs & derivatives , Immunity, Humoral/drug effects , Lectins, C-Type/immunology , Receptors, Cell Surface/immunology , Receptors, Immunologic/immunology , T-Lymphocytes/immunology , Animals , Bacterial Infections/prevention & control , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Dextrans/immunology , Female , Fluorescein-5-isothiocyanate/pharmacology , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Immunoglobulin M/analysis , Immunoglobulin M/immunology , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Liver/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/immunology , Ovalbumin/pharmacology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Spleen/immunology , Vaccination/methods
4.
Immunobiology ; 216(4): 437-46, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20951467

ABSTRACT

Capsular polysaccharides of Streptococcus pneumoniae are representative T-cell-independent type 2 (TI-2) antigens, frequently causing serious infections in children, the elderly, and immunocompromised patients. However, the detailed mechanism of this immune escape by CPSs is poorly understood. To pursue this question, polysaccharide dextran, ligand of SIGN-R1 as well as an appropriate model of the immunogenicity of many TI-2 polysaccharide antigens was used. SIGN-R1 bound to binding immunoglobulin protein (BiP), a well-characterized endoplasmic reticulum (ER) chaperone, primarily in non-ER compartments. Interestingly, SIGN-R1(+) macrophages in the MZ showed high expression of BiP, implying an important role of SIGN-R1 binding to BiP in vivo. To our surprise, dextran is rapidly transported into the ER and subsequently regurgitated out of cells in vitro or in vivo. BiP down-regulation in SIGN-R1 transfectant reduced the regurgitation of dextran, causing the accumulation of dextran in the ER. Therefore, these results demonstrated the first example to describe the intracellular trafficking and the regurgitation of TI-2 antigen dextran, suggesting the novel pathway of TI-2 antigen presentation to immune cells.


Subject(s)
Antigens, T-Independent/immunology , Cell Adhesion Molecules/immunology , Dextrans/immunology , Endoplasmic Reticulum/immunology , Heat-Shock Proteins/immunology , Lectins, C-Type/immunology , Receptors, Cell Surface/immunology , Animals , Biological Transport , Biotin/immunology , Biotin/metabolism , CHO Cells , Cell Line , Cricetinae , Cricetulus , Dendritic Cells, Follicular/immunology , Down-Regulation , Endoplasmic Reticulum Chaperone BiP , Gene Expression Regulation , Intracellular Space/immunology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Binding , Spleen/immunology
5.
Neurosci Lett ; 450(3): 246-51, 2009 Feb 06.
Article in English | MEDLINE | ID: mdl-19095040

ABSTRACT

Although Streptococcus pneumoniae is the major cause of meningitis, how it causes disease is poorly understood. The C-type lectin SIGN-R1 mediates the recently described SIGN-R1 complement activation pathway, which operates against capsular polysaccharides (CPSs) of S. pneumoniae in splenic marginal macrophages. Here, we demonstrate that SIGN-R1, as well as the rat SIGN-R1 homologue CD209b are expressed in most regions of mouse or rat brain, respectively. Moreover, both C-type lectins are obviously expressed on microglia, but not on neurons or astrocytes. We also found that rat CD209b mediates the uptake of dextran or CPS14 within the rat splenic marginal zone, similar to SIGN-R1. On microglia, rat CD209b also mediates the uptake of CPS14 of S. pneumoniae. Our findings strongly suggest that both rat CD209b and SIGN-R1 on microglia mediate the SIGN-R1 complement activation pathway against S. pneumoniae, and thereby plays an important role in the pathogenesis of pneumococcal meningitis.


Subject(s)
Antigens, CD/metabolism , Bacterial Capsules/metabolism , Brain/metabolism , Cell Adhesion Molecules/metabolism , Lectins, C-Type/metabolism , Microglia/metabolism , Receptors, Cell Surface/metabolism , Streptococcus pneumoniae/metabolism , Animals , Brain/microbiology , Brain/physiopathology , Cells, Cultured , Complement Activation/physiology , Female , Meningitis, Pneumococcal/metabolism , Meningitis, Pneumococcal/physiopathology , Mice , Mice, Inbred BALB C , Microglia/microbiology , Microglia/pathology , Rats , Rats, Sprague-Dawley
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