scholarly journals Bone Marrow Dendritic Cells from Mice with an Altered Microbiota Provide Interleukin 17A-Dependent Protection against Entamoeba histolytica Colitis

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Stacey L. Burgess ◽  
Erica Buonomo ◽  
Maureen Carey ◽  
Carrie Cowardin ◽  
Caitlin Naylor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Entamoeba Histolytica ◽  
Murine Model ◽  
Inflammatory Diseases ◽  
Human Microbiome ◽  
Intestinal Bacteria ◽  
Enteric Infection ◽  
Content Type ◽  
Interleukin 17A

ABSTRACTThere is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection.Entamoeba histolyticais a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensalClostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolyticainfection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB+to an SFB−mouse was sufficient to provide protection againstE. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells.IMPORTANCEEntamoeba histolyticais the causative agent of amebiasis, an infectious disease that contributes significantly to morbidity and mortality due to diarrhea in the developing world. We showed in a murine model that colonization with the commensal members of theClostridiaknown as SFB provides protection againstE. histolyticaand that dendritic cells from SFB-colonized mice alone can recapitulate protection. Understanding interactions between enteropathogens, commensal intestinal bacteria, and the mucosal immune response, including dendritic cells, will help in the development of effective treatments for this disease and other infectious and inflammatory diseases. The demonstration of immune-mediated protection due to communication from the microbiome to the bone marrow represents an emerging field of study that will yield unique approaches to the development of these treatments.

Treatment of intracranial gliomas with bone marrow—derived dendritic cells pulsed with tumor antigens

1999 ◽  
Vol 90 (6) ◽  
pp. 1115-1124 ◽  
Author(s):  
Linda M. Liau ◽  
Keith L. Black ◽  
Robert M. Prins ◽  
Steven N. Sykes ◽  
Pier-Luigi DiPatre ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Antigen Presenting Cells ◽  
Content Type ◽  
Cytotoxicity Assays ◽  
Antigen Presenting ◽  
Fine Print

Object. An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of “professional” antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals.Methods. Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte—macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen—pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays.The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen—pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells.Conclusions. Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas, which may serve as a basis for designing clinical trials in patients with brain tumors.

Use of the Immunoproteasome Subunit LMP7 Inhibitor to Ameliorate Gvhd in an MHC-Matched miHA-Disparate Murine Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4106-4106
Author(s):  
Jenny Zilberberg ◽  
Eugenia Dziopa ◽  
Christopher J Kirk ◽  
Robert Korngold
Keyword(s):  
Bone Marrow ◽  
Murine Model ◽  
Research Funding ◽  
Bone Marrow Cells ◽  
Inflammatory Diseases ◽  
Clinical Situation ◽  
Unrelated Donor ◽  
Mhc I ◽  
Split Dose ◽  
Ubiquitin Proteasome

Abstract Abstract 4106 Background: Therapeutic targeting of the ubiquitin-proteasome pathway is currently used for the treatment of multiple myeloma. The immunoproteasome however, is a distinct class of proteasome found predominantly in monocytes and lymphocytes, and it is known to regulate antigen presentation on class I major histocompatibility complexes (MHC-I). ONX 0914 is a LMP7-selective peptide-epoxyketone proteasome inhibitor that is currently in pre-clinical development for the treatment of inflammatory diseases. In the current study, we evaluated the feasibility of using ONX 0914 in the B10.BR→CBA MHC-matched (H2k), minor histocompatibility antigen (miHA)-disparate bone marrow transplantation (BMT) model to decrease the incidence of GVHD. This well established allogeneic BMT model is relevant to the MHC-matched sibling donor or completely matched unrelated donor clinical situation. Methods: To evaluate the effects of ONX 0914 on GVHD, we tested different compound regimens in the model. CBA recipient mice were lethally irradiated (11 Gy, split dose, 4 h apart) and transplanted with 2×106 anti-T cell depleted B10.BR bone marrow cells (ATBM) alone, or in combination with 1×107 enriched B10.BR T cells (GVHD control and ONX 0914 treated groups). ONX 0914 was administrated in full (s.c., once/day at 8 mg/kg) or as a split dose (half dose, twice/day approximately 6 hr apart). Results: Treatment with the ONX 0914 compound significantly improved the survival of mice compared to control GVHD recipients when dosing was performed once/day for three consecutive days (0,1,2 post-BMT) [p = 0.02]. Alternating dosage (days 0,2,4) or daily drug treatment (days 0–4) provided comparable amelioration of GVHD in this model. Conclusion: Our preclinical findings suggest that the immunoproteasome subunit LMP7 is potentially a novel therapeutic target in GVHD as demonstrated by the improved survival rate of recipient mice treated with ONX 0914 in the B10.BR→CBA BMT murine model. Disclosures: Zilberberg: Onyx Pharmaceuticals: Research Funding. Dziopa:Onyx Pharmaceuticals: Research Funding. Korngold:Onyx Pharmaceuticals: Research Funding.

scholarly journals Shikonin inhibits maturation of bone marrow-derived dendritic cells and suppresses allergic airway inflammation in a murine model of asthma

2010 ◽  
Vol 161 (7) ◽  
pp. 1496-1511 ◽  
Author(s):  
Chen-Chen Lee ◽  
Chien-Neng Wang ◽  
Yu-Ting Lai ◽  
Jaw-Jou Kang ◽  
Jiunn-Wang Liao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Airway Inflammation ◽  
Murine Model ◽  
Allergic Airway Inflammation

scholarly journals Enterococcus faecalis Induces Differentiation of Immune-Aberrant Dendritic Cells from Murine Bone Marrow-Derived Stem Cells

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Mohamed Mohamed Elashiry ◽  
Mahmoud Elashiry ◽  
Rana Zeitoun ◽  
Ranya Elsayed ◽  
Fucong Tian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Dendritic Cells ◽  
Enterococcus Faecalis ◽  
Transforming Growth Factor ◽  
Interleukin 4 ◽  
Dependent Manner ◽  
Immune Functions ◽  
Content Type ◽  
Murine Bone Marrow

ABSTRACT Enterococcus faecalis, long implicated in serious systemic infections and failure of root canal treatment, is a persistent inhabitant of oral periapical lesions. Dendritic cells (DCs) and other innate immune cells patrol the oral mucosa for infecting microbes. Dendritic cells are efficient at capturing microbes when immature, whereupon they can transform into potent antigen-presenting cells upon full maturation. Autophagy, a sophisticated intracellular process first described for elimination of damaged organelles, regulates DC maturation and other important immune functions of DCs. The present study examined how E. faecalis influences the differentiation of murine bone marrow-derived stem cells (BMSCs) into functional DCs in the presence of the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Although the viability and differentiation of DCs were not affected by E. faecalis, expression of the autophagy-related proteins ATG7, Beclin1, and LC3bI/II were significantly suppressed in an mTOR-dependent manner. Ultrastructurally, E. faecalis was identified in single-membrane vacuoles, some of which were in the process of binary fission. Bacterium-containing autophagosomes were absent within the cytoplasm. Accessory molecules (major histocompatibility complex class II [MHC-II], CD80, and CD86) and anti-inflammatory cytokine (transforming growth factor β1 [TGF-β1]) were suppressed in E. faecalis-induced DCs, while IL-1β, tumor necrosis factor alpha (TNF-α), and IL-12 levels were upregulated. When pulsed with ovalbumin (OVA), the E. faecalis-induced DCs showed reduction in CD4+ OVA-specific OT-II T cell proliferation. It is concluded that E. faecalis promotes the differentiation of bone marrow stem cells into CD11c-positive DCs with aberrant immune functions while retaining the capability of proinflammatory cytokine induction.

Third Party Cytokine-Induced Killer Cells Protect from Murine Lethal Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3092-3092
Author(s):  
Rie Kuroda ◽  
Shintaro Mase ◽  
Toshihiro Fujiki ◽  
Hideaki Maeba ◽  
Raita Araki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Bone Marrow Cells ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cik Cells ◽  
Marrow Cells

Abstract Cell adoptive immunotherapy protect from lethal graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects is ideal in allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Moreover, the use of third party cells would open a huge source of availability and feasibility across major histocompatibility barriers. In fact, some studies demonstrated that infusion of third party derived cells such as whole bone marrow cells or iNKT cells could ameliorate lethal GVHD in a murine model. Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer and T-cell markers. We have previously reported that donor-type CIK cells have potential to separate graft-versus-tumor effects from GVHD by eliminating host dendritic cells due to the enhanced killing activity by interferon-gamma. Actually, donor-typed CIKs infusion for refractory hematological malignancies after HSCT has been started in some clinical trails. In the present study, we examine the effect of third party cells against GVHD protection, in particular third party CIK cells for prevention from lethal GVHD in a murine model of allogeneic HSCT. To test this, lethally irradiated host Balb/c (H-2d) mice were given C3H (H-2k) or B6 (H-2b) bone marrow cells and splenocytes to induce lethal GVHD with/without third-party cells (C57/BL6 or C3H) such as CIK cells, whole splenocytes, or bone marrow derived dendritic cells (BMDCs) on day 0, which were cultured from bone marrow cells with GM-CSF. Mice receiving third party CIK cells showed much less GVHD and significant survival benefit compared those with third party splenocytes, or BMDCs as shown in the figure below. Interestingly, when infusion of third party splenocytes was delayed until day 4 after bone marrow transplantation, host mice receiving splenocytes survived much better compared with mice receiving splenocytes on day 0, even though reduced number of third party splenocytes was used. This result indicated that timing of third party cell infusion was quite important, especially when third party splenocytes were used. As expected, the mice given reduced number of third CIK cells also showed excellent survival with much less GVHD. Taken together, our results clearly demonstrated that third party CIK cells have strong potential to prevent lethal GVHD without attention to timing of cell infusion. Next, to further investigate the advantage of third party CIK cells rather than whole splenocytes, we compared the hematological reconstitution between the mice given third party CIK cells on day 4 after BMT and whole splenocytes. Both mice showed much less GVHD with the same level, however the recovery of white blood cell count on day 21 after BMT was significantly better in the mice receiving third party CIK cells. In conclusion, infusion of third party CIK cells has strong potential to prevent lethal GVHD with faster hematological recovery after HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Microbial Amyloids Induce Interleukin 17A (IL-17A) and IL-22 Responses via Toll-Like Receptor 2 Activation in the Intestinal Mucosa

2012 ◽  
Vol 80 (12) ◽  
pp. 4398-4408 ◽  
Author(s):  
Jessalyn H. Nishimori ◽  
Tiffanny N. Newman ◽  
Gertrude O. Oppong ◽  
Glenn J. Rapsinski ◽  
Jui-Hung Yen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Intestinal Mucosa ◽  
Amyloid Fibrils ◽  
Inflammatory Responses ◽  
Toll Like Receptor ◽  
T Helper ◽  
Content Type ◽  
Interleukin 17A ◽  
Toll Like Receptor 2

ABSTRACTThe Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phylaFirmicutes,Bacteroidetes, andProteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogenSalmonella entericaserotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. AcsgBAmutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to theS. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL-22 expression was blunted duringS. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent mannerin vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations—CD4+T helper cells, cytotoxic CD8+T cells, and γδ T cells—produced IL-17A in response to curli fibrils in the intestinal mucosa duringS. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa.

scholarly journals Effect of Poli I:C in murine model of autoimmune thyroiditis

2015 ◽  
Author(s):  
Carolina Loreto Vera Sepulveda ◽  
MIguel Barria Maldonado
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Murine Model ◽  
Autoimmune Thyroiditis ◽  
Hashimoto’S Thyroiditis ◽  
Inflammatory Diseases ◽  
Hashimoto's Thyroiditis ◽  
Autoimmune And Inflammatory Diseases

Hashimoto's thyroiditis is one of the most common autoimmune diseases in humans and, similar to other autoimmune diseases, is multifactorial in nature. Moreover, the expression of TLRs has been implicated in the pathogenesis of autoimmune and inflammatory diseases, such as diabetes and insulinitis. The TLRs are a family of at least 10 receptors associated with innate immunity that are present in monocytes, macrophages, and dendritic cells, which recognize highly conserved patterns of the surface of microorganisms, such as LPS, peptidoglycan, and dsRNA and CpG sequences.

scholarly journals Toll-Like Receptor 9-Dependent Activation of Bone Marrow-Derived Dendritic Cells byURA5DNA from Cryptococcus neoformans

2011 ◽  
Vol 80 (2) ◽  
pp. 778-786 ◽  
Author(s):  
Misuzu Tanaka ◽  
Keiko Ishii ◽  
Yuri Nakamura ◽  
Akiko Miyazato ◽  
Atsuko Maki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
High Dose ◽  
Apparent Difference ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Content Type ◽  
Cpg Motif

ABSTRACTCryptococcus neoformansis an opportunistic fungal pathogen that causes meningoencephalitis in immunocompromised patients. Recently, we reported that Toll-like receptor 9 (TLR9) is involved in host defense againstC. neoformans: specifically, it detects the pathogen's DNA. In the present study, we aimed to elucidate the mechanisms underlying TLR9-mediated activation of innate immune responses by using theURA5gene, which encodes a virulent component of this fungal pathogen. A PCR-amplified 345-bpURA5gene fragment induced interleukin-12 p40 (IL-12p40) production by bone marrow-derived dendritic cells (BM-DCs) in a TLR9-dependent manner. Similar activity was detected in the 5′ 129-bp DNA fragment ofURA5and in a synthesized oligodeoxynucleotide (ODN) with the same sequence. Shorter ODN fragments, which contained GTCGGT or GACGAT but had only 24 or 21 bases, induced IL-12p40 production and CD40 expression by BM-DCs, but this activity vanished when the CG sequence was replaced by GC or when a phosphorothioate modification was introduced. IL-12p40 production caused by active ODN was strikingly enhanced by treatment with DOTAP, a cationic lipid that increases the uptake of DNA by BM-DCs, though DOTAP failed to induce IL-12p40 production by inactive ODN and did not affect the activity of an ODN-containing canonical CpG motif. There was no apparent difference in intracellular trafficking between active and inactive ODNs. Finally, an extremely high dose of inactive ODN suppressed IL-12p40 production by BM-DCs that had been stimulated with active ODN. These results suggest that theC. neoformansURA5gene activates BM-DCs through a TLR9-mediated signaling pathway, using a mechanism possibly independent of the canonical CpG motif.

scholarly journals Leptin Receptor Mutation Results in Defective Neutrophil Recruitment to the Colon during Entamoeba histolytica Infection

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Caitlin Naylor ◽  
Stacey Burgess ◽  
Rajat Madan ◽  
Erica Buonomo ◽  
Khadija Razzaq ◽  
...  
Keyword(s):  
Entamoeba Histolytica ◽  
Leptin Receptor ◽  
Neutrophil Infiltration ◽  
Neutrophil Function ◽  
Enteric Infection ◽  
Neutrophil Chemotaxis ◽  
Content Type ◽  
Innate Defense ◽  
The Impact ◽  
Increased Susceptibility

ABSTRACTAmebiasis is an enteric infection caused byEntamoeba histolytica, with symptoms ranging in severity from asymptomatic colonization to dysentery. Humans with the Q223R leptin receptor mutation have increased susceptibility to amebiasis, but the mechanism has been unclear. Using a mouse model expressing the mutation, we tested the impact of the Q223R mutation on the innate immune response toE. histolyticainfection. The 223R mutation resulted in delayed clearance of amebae from the cecum, as had been previously observed. We found that neutrophil influx to the site of the infection was reduced 12 h after infection in 223R mice. Depletion of neutrophils with anti-Ly6G monoclonal antibody increased susceptibility of wild-type mice to infection, supporting the importance of neutrophils in innate defense. Leptin expression was increased in the cecum byE. histolyticainfection, suggesting that leptin could serve as a homing signal for neutrophils to the gut. Interestingly, neutrophils from mice with the 223R mutation had diminished chemotaxis toward leptin. This impaired chemotaxis likely explained the reduced gut infiltration of neutrophils. The newly recognized effect of the leptin receptor Q223R mutation on neutrophil chemotaxis and the impact of this mutation on multiple infectious diseases suggest a broader impact of this mutation on susceptibility to disease.IMPORTANCEThe Q223R leptin receptor mutation results in increased susceptibility of children and adults toE. histolytica, one of the leading causes of diarrhea morbidity and mortality in children of the developing world. Here we show that the mutation results in reduced neutrophil infiltration to the site of infection. This decreased infiltration is likely due to the mutation’s impact on neutrophil chemotaxis toward leptin, an inflammatory agent upregulated in the cecum after infection. The significance of this work thus extends beyond understandingE. histolyticasusceptibility by also providing insight into the potential impact of leptin on neutrophil function in other states of altered leptin signaling, which include both malnutrition and obesity.

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