scholarly journals A novel plasma membrane-phillic graphene oxide nanocarrier for neuropeptide delivery to generate tolerogenic dendritic cells in GVHD Immunotherapy

2021 ◽  
Author(s):  
Xiaohui Wang ◽  
Sujing Sun ◽  
Chulin He ◽  
Chenyan Li ◽  
Wenyuan Bai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Graphene Oxide ◽  
Lymph Nodes ◽  
Migration Ability ◽  
Hematopoietic Stem ◽  
Creb Phosphorylation ◽  
In Vivo Experiments ◽  
Tolerogenic Dendritic Cells ◽  
Cytoskeleton Reorganization

Abstract The prevention and the treatment of graft-versus-host disease (GVHD) remains a barrier to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Tolerogenic dendritic cells (TDCs) have become a hotspot in GVHD prevention despite the poor induction efficiency. Herein, we designed a novel size-dependent platform of graphene oxide (GO) nanosheets for neuropeptide delivery for the purpose of TDC generation. GO with a lateral size༞1 µm (L-GO) showed strong affinities to DC membrane, which effectively promoted the recognition between neuropeptide, urocortin (UCN) and its receptor CRHR2 and in turn benefited TDC generation through PKA C/CREB phosphorylation. Simultaneously, L-GO also elevated the expression of CCR7 and enhanced the migration ability of TDCs by mediating cytoskeleton reorganization. In vivo experiments offered direct evidence that TDCs inducted by UCN@L-GO exhibited efficient migration to lymph nodes, abundant generation of Treg, a significant decrease of proinflammatory cytokines and in turn excellent efficiency in GVHD relief. In the current study, we proposed an innovative GO nanosheets based cytomembrane-targeted platform for neuropeptide delivery and subsequent TDC generation. In the meantime, the promoted mobility of TDC pulsed by GOs ensured the high homing efficiency to secondary lymph nodes, attributing to GVHD treatment in vivo. Thus, such work provided a promising strategy that might be applicable more broadly to delivery systems for receptor-mediated drugs, and could meet the changing demand of nanotechnology-based immunotherapy.

Endothelial stroma programs hematopoietic stem cells to differentiate into regulatory dendritic cells through IL-10

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1189-1197 ◽  
Author(s):  
Hua Tang ◽  
Zhenhong Guo ◽  
Minghui Zhang ◽  
Jianli Wang ◽  
Guoyou Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Regulatory Function ◽  
Hematopoietic Stem ◽  
Regulatory Dendritic Cells

Abstract Regulatory dendritic cells (DCs) have been reported recently, but their origin is poorly understood. Our previous study demonstrated that splenic stroma can drive mature DCs to proliferate and differentiate into regulatory DCs, and their natural counterpart with similar regulatory function in normal spleens has been identified. Considering that the spleen microenvironment supports hematopoiesis and that hematopoietic stem cells (HSCs) are found in spleens of adult mice, we wondered whether splenic microenvironment could differentiate HSCs into regulatory DCs. In this report, we demonstrate that endothelial splenic stroma induce HSCs to differentiate into a distinct regulatory DC subset with high expression of CD11b but low expression of Ia. CD11bhiIalo DCs secreting high levels of TGF-β, IL-10, and NO can suppress T-cell proliferation both in vitro and in vivo. Furthermore, CD11bhiIalo DCs have the ability to potently suppress allo-DTH in vivo, indicating their preventive or therapeutic perspectives for some immunologic disorders. The inhibitory function of CD11bhiIalo DCs is mediated through NO but not through induction of regulatory T (Treg) cells or T-cell anergy. IL-10, which is secreted by endothelial splenic stroma, plays a critical role in the differentiation of the regulatory CD11bhiIalo DCs from HSCs. These results suggest that splenic microenvironment may physiologically induce regulatory DC differentiation in situ.

scholarly journals Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity

2021 ◽  
Vol 118 (3) ◽  
pp. e2021364118
Author(s):  
Hannah L. Miller ◽  
Prabhakar Sairam Andhey ◽  
Melissa K. Swiecki ◽  
Bruce A. Rosa ◽  
Konstantin Zaitsev ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Diphtheria Toxin ◽  
Fluorescein Isothiocyanate ◽  
Skin Inflammation ◽  
Contact Hypersensitivity ◽  
Type I ◽  
Th2 Response ◽  
Draining Lymph Nodes

Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.

scholarly journals Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells

2018 ◽  
Vol 215 (9) ◽  
pp. 2265-2278 ◽  
Author(s):  
Colleen M. Lau ◽  
Ioanna Tiniakou ◽  
Oriana A. Perez ◽  
Margaret E. Kirkling ◽  
George S. Yap ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cd8 T Cells ◽  
Functional Differentiation ◽  
Specific Gene ◽  
Hematopoietic Stem

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.

scholarly journals Low-dose 2-deoxy glucose stabilises tolerogenic dendritic cells and generates potent in vivo immunosuppressive effects

2020 ◽  
Author(s):  
M. Christofi ◽  
S. Le Sommer ◽  
C. Mölzer ◽  
I. P. Klaska ◽  
L. Kuffova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Low Dose ◽  
Aerobic Glycolysis ◽  
Subcutaneous Administration ◽  
Lactate Production ◽  
Mycobacterial Antigen ◽  
Mouse Bone Marrow ◽  
Tolerogenic Dendritic Cells

Abstract Cell therapies for autoimmune diseases using tolerogenic dendritic cells (tolDC) have been promisingly explored. A major stumbling block has been generating stable tolDC, with low risk of converting to mature immunogenic DC (mDC), exacerbating disease. mDC induction involves a metabolic shift to lactate production from oxidative phosphorylation (OXPHOS) and β-oxidation, the homeostatic energy source for resting DC. Inhibition of glycolysis through the administration of 2-deoxy glucose (2-DG) has been shown to prevent autoimmune disease experimentally but is not clinically feasible. We show here that treatment of mouse bone marrow-derived tolDC ex vivo with low-dose 2-DG (2.5 mM) (2-DGtolDC) induces a stable tolerogenic phenotype demonstrated by their failure to engage lactate production when challenged with mycobacterial antigen (Mtb). ~ 15% of 2-DGtolDC express low levels of MHC class II and 30% express CD86, while they are negative for CD40. 2-DGtolDC also express increased immune checkpoint molecules PDL-1 and SIRP-1α. Antigen-specific T cell proliferation is reduced in response to 2-DGtolDC in vitro. Mtb-stimulated 2-DGtolDC do not engage aerobic glycolysis but respond to challenge via increased OXPHOS. They also have decreased levels of p65 phosphorylation, with increased phosphorylation of the non-canonical p100 pathway. A stable tolDC phenotype is associated with sustained SIRP-1α phosphorylation and p85-AKT and PI3K signalling inhibition. Further, 2-DGtolDC preferentially secrete IL-10 rather than IL-12 upon Mtb-stimulation. Importantly, a single subcutaneous administration of 2-DGtolDC prevented experimental autoimmune uveoretinitis (EAU) in vivo. Inhibiting glycolysis of autologous tolDC prior to transfer may be a useful approach to providing stable tolDC therapy for autoimmune/immune-mediated diseases.

scholarly journals Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1291 ◽  
Author(s):  
Ritprajak ◽  
Kaewraemruaen ◽  
Hirankarn
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Ex Vivo ◽  
Immunosuppressive Drugs ◽  
Clinical Implications ◽  
Systemic Lupus ◽  
Tolerogenic Dendritic Cells

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

Human Conventional and Plasmacytoid Dendritic Cells Can Originate from Both Lymphoid and Myeloid Progenitors in a New Humanized Mouse System.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2273-2273
Author(s):  
Fumihiko Ishikawa ◽  
Tadafumi Iino ◽  
Hiroaki Niiro ◽  
Shuro Yoshida ◽  
Toshihiro Miyamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cells ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Transcription Profiles ◽  
Human Dendritic Cells ◽  
Myeloid Progenitors

Abstract Dendritic cells play a key role in host defense by presenting exogenous antigens to T cells. Two dendritic cell subsets, conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), express distinct repertoire of Toll-like-receptors and recognize different antigens. We previously reported that murine cDCs and pDCs differentiate via either the myeloid or the lymphoid pathway (Shigematsu et al. Immunity ). It is, however, still unclear whether human cDCs and pDCs develop from myeloid, lymphoid or both lineages. In order to analyze the in vivo differentiation of human dendritic cells, we employed the newly-developed xenotrasplant assay system which utilizes newborn NOD-scid/IL2rgnull mice (Ishikawa et al., Blood, in press). Transplantation of 104 Lin-CD34+CD38- hematopoietic stem cells into sublethally irradiated newborn NOD-scid/IL2rgnull mice resulted in generation of all hematopoietic and lymphoid components for a long-term via physiological intermediates such as common myeloid progenitors (CMP) and common lymphoid progenitors (CLP). We found that in this system, dendritic cell subcomponents such as hCD11c+hIL3Ralow cDCs and hCD11c-hIL3Rahigh pDCs, efficiently developed in recipients’ bone marrow, spleen and peripheral blood. To elucidate the origin of human mDCs and pDCs, we purified CMP or CLP from the cord blood, and transplanted these cells into sublethally irradiated newborn NOD-scid/IL2rgnull mice via facial vein. At 4-6 weeks post-transplantation, CMP gave rise only to myeloid cells such as erythroid cells, platelets and granulocytes, while CLP exclusively generated T, B and NK cells. Interestingly, in either mouse group injected with CMP or CLP, cDCs and pDCs were easily detected in the spleen and in the bone marrow. Phenotypic and RT-PCR analyses of purified CMP- or CLP-derived DCs revealed that DCs possessed similar phenotypic characteristics, and transcription profiles in TLR families, BDCA antigens and costimulation molecules, irrespective of their lineage origin. Thus, human cDCs and pDCs develop through both myeloid and lymphoid pathways as in case of mouse hematopoiesis. Further characterization of DCs of different lineage origin is currently performed by microarray analyses in order to find genes specifically expressed in each DC subset.

Potent Strategy for Treatmet of Gvhd and Autoimmune-Diseased by Infusion of Donor-Typed or Even Third-Party Tolerogenic Dendritic Cells by Psoralen Plus UVA Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2777-2777
Author(s):  
Hideaki Maeba ◽  
Ryosei Nishimura ◽  
Rie Kuroda ◽  
Raita Araki ◽  
Shintaro Mase ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Neutralizing Antibodies ◽  
Conflicts Of Interest ◽  
Third Party ◽  
Cell Contact ◽  
Dependent Manner ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Tolerogenic Dendritic Cells ◽  
Inhibition Of Alloreaction

Abstract Abstract 2777 We have reported that bone marrow derived dendritic cells with psoralen and UVA (PUVA-DCs) treatment acquired tolerogenicity in mice. With the purpose of potential application of PUVA-DCs in a clinical hematopoietic stem cell transplantations (HSCT) for graft-versus-host disease (GVHD), we showed that mixed lymphocyte reaction (MLR) was strongly inhibited when PUVA-DCs from the stimulator strain were added to the coculture (Stimulator (S): conventional DCs obtained from C57BL/6, Responder (R): splenocytes obtained from Balb/c, PUVA-DCs: C57BL/6). This suggests that infusion of host-typed PUVA-DCs would become a novel therapeutic approach for GVHD. However utilizing host-typed DCs has problems because of leukemic cell contaminations or low efficiency of cell culture from the patients receiving repetitive chemotherapy. Therefore next concern is whether PUVA-DCs generated from BM donor or even strangers would have same tolerogenicity as host-typed PUVA-DCs do. To test this, we performed MLR by adding PUVA-DC generated from the same strain of responder or third party strain (S: conventional DCs obtained from C57BL/6, R: splenocytes obtained from Balb/c, PUVA-DC: C57BL/6 or C3H). Proliferation was significantly inhibited when PUVA-DC generated from the stimulator strain were added to the coculture (p<0.05). Also significant inhibition was observed (p<0.05) when adding PUVA-DCs generated from third party, suggesting that PUVA-DCs have tolerogenicity in a MHC-independent manner. To clarify the mechanisms of how PUVA-DCs induce tolerogenicity, we performed MLR as mentioned above with the addition of neutralizing antibodies against IL-10 or TGF-beta1 or both, which have immunosuppressive effects. Neutralization of immunosuppressive cytokines had no effects on MLR. We then hypothesized that cell-to-cell contact between PUVA-DCs and alloreactive T-cells was needed to mediate the regulatory effect. To this end, we performed MLR using transwell to prevent cell-to cell contact. MLR was not suppressed when transwell was used, suggesting that PUVA-DCs dominantly regulates the alloreaction in a cell contact-dependent manner. This is the first report that PUVA-DCs prepared not only from host-typed but from donor-typed or even third-party could induce strong inhibition of alloreaction. Tolerogenic DCs prepared previously by several ways could not induce inhibition of alloreaction in vitro when these cells were prepared from donor-typed or third-party strains in mice. To apply tolerogenic dendritic cells for GVHD in clinical settings, it is necessary to obtain sufficient doses of PUVA-DCs with ease and safety guaranteed. Therefore in the future PUVA-DCs generated even from HLA mismatched iPS cells would be a promising approach. In conclusion, infusion of PUVA-DCs from donor-typed or even third party strain could have a potent strategy for treatment of lethal GVHD and autoimmune diseases. Disclosure: No relevant conflicts of interest to declare.

In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles

2006 ◽  
Vol 112 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Sai T. Reddy ◽  
Annemie Rehor ◽  
Hugo G. Schmoekel ◽  
Jeffrey A. Hubbell ◽  
Melody A. Swartz
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Poly Propylene

scholarly journals Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1727
Author(s):  
Jun-Ho Lee ◽  
So-Yeon Choi ◽  
Soo-Yeoun Park ◽  
Nam-Chul Jung ◽  
Kyung-Eun Noh ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Cancer Vaccines ◽  
Biological Effects ◽  
Migratory Capacity ◽  
Migration Capacity ◽  
Antigen Presenting ◽  
Si Rna ◽  
Secondary Lymphoid Organs

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

Sign in / Sign up

Export Citation Format

Share Document