scholarly journals Tolerogenic Dendritic Cells Attenuate Experimental Autoimmune Antimyeloperoxidase Glomerulonephritis

2019 ◽  
Vol 30 (11) ◽  
pp. 2140-2157 ◽  
Author(s):  
Dragana Odobasic ◽  
Virginie Oudin ◽  
Kenji Ito ◽  
Poh-Yi Gan ◽  
A. Richard Kitching ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Bone Marrow Cells ◽  
Therapeutic Option ◽  
Promising Tool ◽  
Inducible Costimulator ◽  
Tolerogenic Dendritic Cells

Background Because of their capacity to induce antigen-specific immunosuppression, tolerogenic dendritic cells are a promising tool for treatment of autoimmune conditions, such as GN caused by autoimmunity against myeloperoxidase (MPO).MethodsWe sought to generate tolerogenic dendritic cells to suppress anti-MPO GN by culturing bone marrow cells with an NFκB inhibitor (BAY 11-7082) and exposing them to a pulse of MPO. After administering these MPO/BAY dendritic cells or saline to mice with established anti-MPO or anti–methylated BSA (mBSA) immunity, we assessed immune responses and GN. We also examined mechanisms of action of MPO/BAY dendritic cells.ResultsMPO/BAY dendritic cells decreased anti-MPO immunity and GN without inhibiting immune responses against mBSA; they also induced IL-10–producing regulatory T cells in MPO-immunized mice without affecting IL-10+ CD4+Foxp3− type 1 regulatory T cells or regulatory B cells. MPO/BAY dendritic cells did not inhibit anti-MPO immunity when CD4+Foxp3+ cells were depleted in vivo, showing that regulatory T cells are required for their effects. Coculture experiments with dendritic cells and CD4+Foxp3− or CD4+Foxp3+ cells showed that MPO/BAY dendritic cells generate Foxp3+ regulatory T cells from CD4+Foxp3− cells through several pathways, and induce IL-10+ regulatory T cells via inducible costimulator (ICOS), which was confirmed in vivo. Transfer of MPO/BAY dendritic cell–induced regulatory T cells in vivo, with or without anti–IL-10 receptor antibody, demonstrated that they suppress anti-MPO immunity and GN via IL-10.ConclusionsMPO/BAY dendritic cells attenuate established anti-MPO autoimmunity and GN in an antigen-specific manner through ICOS-dependent induction of IL-10–expressing regulatory T cells. This suggests that autoantigen-loaded tolerogenic dendritic cells may represent a novel antigen-specific therapeutic option for anti-MPO GN.

scholarly journals CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

2003 ◽  
Vol 198 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Guillaume Oldenhove ◽  
Magali de Heusch ◽  
Georgette Urbain-Vansanten ◽  
Jacques Urbain ◽  
Charlie Maliszewski ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Peripheral Tolerance ◽  
T Helper Cell ◽  
Helper Cell ◽  
T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

scholarly journals Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

2018 ◽  
Author(s):  
Thi Thu Phuong Tran ◽  
Karsten Eichholz ◽  
Patrizia Amelio ◽  
Crystal Moyer ◽  
Glen R Nemerow ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Persistent Infections ◽  
Cell Immunity ◽  
Tolerogenic Dendritic Cells ◽  
Antigen Presenting ◽  
Tolerogenic Dcs

AbstractFollowing repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregsare generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.Author summaryWhile numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus–antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.

scholarly journals Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo

2006 ◽  
Vol 203 (3) ◽  
pp. 505-511 ◽  
Author(s):  
Carlos E. Tadokoro ◽  
Guy Shakhar ◽  
Shiqian Shen ◽  
Yi Ding ◽  
Andreia C. Lino ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Laser Scanning ◽  
Laser Scanning Microscopy ◽  
Early Effect ◽  
Two Photon

Regulatory T (T reg) cells exert powerful down-modulatory effects on immune responses, but it is not known how they act in vivo. Using intravital two-photon laser scanning microscopy we determined that, in the absence of T reg cells, the locomotion of autoantigen-specific T cells inside lymph nodes is decreased, and the contacts between T cells and antigen-loaded dendritic cells (DCs) are of longer duration. Thus, T reg cells can exert an early effect on immune responses by attenuating the establishment of stable contacts during priming of naive T cells by DCs.

Suppression of the Immune Response to Human FVIII with FVIII Transgene Modified Tolerogenic Dendritic Cells in Hemophilic Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 591-591
Author(s):  
Rui-Jun Su ◽  
Angela Epp ◽  
Xiaoping Wu ◽  
Neil Josephson
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Tolerogenic Dendritic Cells

Abstract The development of anti-factor VIII (FVIII) inhibitory antibodies is currently the most significant complication of FVIII replacement therapy in the management of patients with hemophilia A. Infusion of in vitro generated tolerogenic dendritic cells (tDCs) loaded with foreign antigen has been shown to promote durable antigen-specific tolerance in vivo through mechanisms that involve the induction of regulatory T cells. In this study we evaluated the ability of tDCs transduced with a human B domain deleted FVIII transgene-expressing foamy virus (FV) vector to modulate the immune response to human FVIII in both naïve and pre-immunized hemophilia A mice. The tDCs were generated by flow sorting the population of CD11clowCD45RBhigh cells produced in culture of lineage negative bone marrow cells in RPMI1640/10%FBS supplemented with IL-10 and the neural peptides VIP and PACAP38. Expression of co-stimulatory molecules CD80 and CD86 and MHC Class II was negative or low on the generated tDCs and these cells remained un-activated even after stimulation with LPS or transduction by FV vectors. These tDCs produced low levels of IL-6 and TNF-α, and high level of IL-10. Furthermore, co-culture of the vector transduced tDCs with FVIII stimulated effector T cells (Teffs) resulted in decreased proliferation of Teffs and reduced secretion of IFN-γ and IL-2. In the cultures with the transduced tDCs there was also an increase in the number of apoptotic Teffs. Naïve Balb/c hemophilia A mice were treated with 2 weekly infusions of FVIII vector transduced tDCs (tDC-F8), control tDCs (tDCs-Ctrl), or no cells (Neg-Ctrl) prior to being challenged with four weekly intravenous doses of 0.2 μg rhFVIII. Following immunization the total cellularity and weights of spleens harvested from tDC-F8 mice were consistently half that of spleens from either tDC-Ctrl or Neg-Ctrl mice. Furthermore, inhibitor titers in tDC-F8 mice were 60–61% lower than either Neg-Ctrl or tDC-Ctrl mice (p < 0.05 compared to both controls). The regulatory T cell related markers FOXP3, CD25, CD103, CTLA4 and GITR were all up-regulated on splenic CD4+ T cells from tDC-F8 mice and the CD4+ T cell proliferation response to FVIII stimulation in splenocytes from tDC-F8 mice was suppressed by approximately 90%. Moreover, the rate of apoptosis in splenic T cells from tDC-F8 mice was 33% higher than splenic T cells from either Neg-Ctrl or tDC-Ctrl mice. In pre-immunized mice, treatment with 4 weekly infusions of FVIII vector transduced tDCs lowered inhibitor titers by 54% compared to no treatment controls (p < 0.05). In contrast, treatment with untransduced tDCs had no significant effect on the inhibitor titers of pre-immunized mice. Importantly, adoptive transfer of CD4+ T cells from tDC-8 mice produced suppression of the immune response to FVIII in subsequently immunized naïve secondary recipients.. In summary, these data indicate that FVIII vector transduced tDCs are useful in suppressing the immune response to FVIII in hemophilia A mice and suggest that regulatory T cells play a role in the induced immune modulation. More in vivo studies are in progress to confirm the durability of these effects. Future studies will also focus on isolating and characterizing the regulatory T cell populations induced by in vivo administration of transgene modified tDCs.

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