scholarly journals A murine Staphylococcus aureus fracture-related infection model characterised by fracture non-union, staphylococcal abscess communities and myeloid-derived suppressor cells

2021 ◽  
Vol 41 ◽  
pp. 774-792
Author(s):  
MI Hofstee ◽  
◽  
M Riool ◽  
F Gieling ◽  
V Stenger ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Marrow ◽  
T Cells ◽  
Cellular Response ◽  
Bone Fractures ◽  
Suppressor Cells ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Post Surgery ◽  
Over Time

A fracture-related infection (FRI) is a serious complication that can occur after surgical fixation of bone fractures. Affected patients may encounter delayed healing and functional limitations. Although it is well established that Staphylococcus aureus (S. aureus) is the main causative pathogen of an FRI, the pathophysiology of an S. aureus-induced FRI is not well characterised over time. Therefore, an experimental study in mice comparing S. aureus-inoculated and non-inoculated groups was performed that particularly focused on staphylococcal abscess communities (SACs) and host cellular response. C57Bl/6N female mice received a double osteotomy of the femur, which was stabilised using a titanium 6-hole MouseFix locking plate and four screws. Animals were either S. aureus-inoculated or non-inoculated and euthanised between 1 and 28 d post-surgery. Histopathological evaluation showed normal bone healing for non-inoculated mice, whereas inoculated mice had no fracture consolidation and severe osteolysis. Within the bone marrow of inoculated mice, SACs were observed from 7 d, which increased in size and number over time. A fibrin pseudocapsule enclosed the SACs, which were surrounded by many Ly6G+ neutrophils with some Ly6C+ monocytes and F4/80+ macrophages, the majority of which were viable. The abscesses were encapsulated by fibrin(ogen), collagen and myofibroblasts, with regulatory T cells and M2 macrophages at the periphery. Only bone marrow monocytes and neutrophils of inoculated mice displayed functional suppression of T cells, indicative of myeloid-derived suppressor cells. The present study revealed that an FRI in mice is persistent over time and associated with osteolysis, SAC formation and an immunosuppressive environment.

Increased Population Of Myeloid-Derived Suppressor Cells In Patients With Myelodysplastic Syndromes Overexpress ARG1 and Mediate CD8+ T Cell Inhibition

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5212-5212 ◽  
Author(s):  
Zonghong Shao ◽  
Huijuan Jiang ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Myelodysplastic Syndromes ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Normal Controls ◽  
Apoptosis Ratio

Abstract Objective To investigate the proportion and activation of myeloid- derived suppressor cells (MDSC) in bone marrow from patients with myelodysplastic syndromes (MDS). Methods The proportion of MDSC (Lin-HLA-DR-CD33+) in bone marrow of 30 MDS patients and 19 normal controls were measured by flow cytometry assay(FCM). MDSC and CD8+ T cell were isolated from bone marrow of 14 MDS patients and 14 normal controls among them by FCM and microbeads. The expressions of arginase 1(ARG1) and inducible nitric oxide synthase (iNOS) were analyzed by qPCR and western bolting. Co-cultures with CD8+ T cell were proved the MDSC-mediated inhibition of CD8+ T cell. Results MDS patient’s median MDSC were 7.29% which was higher than that of controls (2.91%). The expression of ARG1 and iNOS mRNA in MDSC of high-risk MDS patients was higher than that of low-risk MDS patients. But the protein of ARG1 was overexpressed rather than that of iNOS. After co-cultured, the apoptosis ratio of CD8+ T cells of MDS((64.17±4.86) %) was increased compared to pure CD8+ T cells ( (54.58±9.95)%). Further more, the production of IFN-γsecreted by CD8+ T cells co-cultured with MDSC ((551.94±47.39) pg/ml)was lower than that of pure CD8+ T cells ((586.04±46.65) pg/ml) There was no significant difference in level of TNF-βbetween co-cultured with MDSC and pure CD8+ cells. Conclusion The proportion of MDSC in bone marrow was increased significantly in MDS. MDSC overexpressed ARG1 in patients with MDS and correlated to the malignant degree of this disease. Further more, MDSC can increased the apoptosis ratio of CD8+ T cell, and inhibited the secretion of IFN-γ. These findings suggested MDSC mediated the response of immunosuppression in MDS. Disclosures: No relevant conflicts of interest to declare.

Administration Of An Oral PDE5 Inhibitor, Tadalafil In Conjunction With a Lenalidomide Containing Regimen In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Nilanjan Ghosh ◽  
Lakshmi Rudraraju ◽  
Xiaobu Ye ◽  
Kimberly Noonan ◽  
Carol Ann Huff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Pde5 Inhibitor ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Prior Therapy ◽  
Gi Bleed ◽  
Phosphodiesterase 5

Abstract Increasing tumor burden has been associated with an immunosuppressive network posing a significant barrier to anti-tumor immunity. Amongst these pathways, myeloid derived suppressor cells (MDSCs) play a critical role in suppressing immune function through upregulation of iNOS and arginase-1 (Arg1). There is evidence of increased MDSCs in patients with multiple myeloma compared to healthy donors [1]. Additionally, it has been shown that MDSCs regulate the growth of myeloma by inhibiting T cells in the bone marrow [2]. We therefore hypothesized that inhibiting MDSCs could augment the anti-tumor activity of the immunomodulatory drug lenalidomide. We have shown previously that phosphodiesterase 5 inhibitors such as tadalafil effectively inhibit MDSC function through downregulation of iNOS and Arg-1 production [3]. To prospectively study the effect of MDSC inhibition in myeloma, we initiated a clinical trial in patients who were refractory to lenalidomide-based regimens, with the oral PDE5 inhibitor, tadalafil, added to their lenalidomide-containing regimen. Refractory to lenalidomide containing regimen was defined as disease progression within 60 days of lenalidomide/dexamethasone (Rd) or Biaxin/lenalidomide/dexamethasone (BiRd). Responses were monitored by International Myeloma Working Group (IMWG) criteria. 13 patients were enrolled between April 2012 and March 2013. Median age was 63, 46.1% female, median number of prior therapies was 4 (range 3-10), 10 patients (80%) had BiRd as their immediate prior therapy, 3 (20%) patients had Rd as the immediate prior therapy, 4 (30.8%) patients had high risk cytogenetics/FISH, 4 (30.8%) patients had ISS III disease and 5 (38.4%) patients had a stem cell transplant in the past. 2 patients were not evaluable, 1 did not meet the eligibility criteria and another patient with a history of gastrointestinal (GI) bleed came off protocol in less than a week because of a recurrent GI bleed. 1 (9%) patient had a minor response (MR) lasting 3 months, 4 (36.4%) patients achieved stable disease (SD), 6 (54.5%) patients developed progressive disease (PD). For patients who achieved SD, the median duration was 66 days (range 48-161 days). Median PFS was 48 days (95% CI 25-71 days). 2 (18.1%) patients needed dose reduction of tadalafil for grade 3 back pain, which was the only toxicity attributable to the drug. There were no deaths on study. At a median follow up of 1 year, the OS is 81.8%. The trial met early stopping rule due to lack of response. Biologic correlates were performed pre and post treatment and included measurement of MDSCs numbers by flow cytometry using CD14+, CD33+, HLADRlow, IL4Rα+ or CD15+, CD33+, HLADRlow, IL4Rα+. Interestingly, MDSCs were not detected in any of the patients at baseline in both blood and marrow and this correlated with the lack of clinical response. In mice, lenalidomide can reduce MDSC numbers [4]. All patients on this trial were heavily pre-treated with lenalidomide for a median duration of 783 days (range 55-1741 days) which could explain the low numbers of MDSCs at enrollment. Strategies aimed at inhibiting MDSC function would be best tested in patients who have elevated levels of MDSCs by flow cytometry. References 1. Gorgun, G.T., et al., Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood, 2013. 121(15): p. 2975-87. 2. Ramachandran, I.R., et al., Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol, 2013. 190(7): p. 3815-23. 3. Serafini, P., et al., Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med, 2006. 203(12): p. 2691-702. 4. Sakamaki, I., et al., Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas. Leukemia, 2013. Disclosures: Off Label Use: Tadalafil for supression of myeloid derived suppressor cells.

scholarly journals GMI, an Immunomodulatory Peptide from Ganoderma microsporum, Restrains Periprosthetic Joint Infections via Modulating the Functions of Myeloid-Derived Suppressor Cells and Effector T Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 6854
Author(s):  
Kuo-Ti Peng ◽  
Jiun-Liang Chen ◽  
Liang-Tseng Kuo ◽  
Pei-An Yu ◽  
Wei-Hsiu Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Bacterial Infections ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Effector T Cells ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Beneficial Effects ◽  
Joint Infections ◽  
Tnf Α

Periprosthetic joint infections (PJIs) caused by Staphylococcus aureus infection are difficult to treat due to antibiotic resistance. It is known that the biofilms from methicillin-resistant S. aureus (MRSA) promote expansion of myeloid-derived suppressor cells (MDSCs) to suppress T-cell proliferation and benefit bacterial infections. This study finds that GMI, a fungal immunomodulatory peptide isolated from Ganoderma microsporum, suppresses MDSC expansion to promote the proliferation of cytotoxic T cells. The enhancement is likely attributed to increased expression of IL-6 and TNF-α and reduction in ROS expression. Similar beneficial effects of GMI on the suppression of MDSC expansion and IL-6 expression are also observed in the whole blood and reduces the accumulation of MDSCs in the infected bone region in a mouse PJI infection model. This study shows that GMI is potentially useful for treating S. aureus-induced PJIs.

scholarly journals In Vitro 3D Staphylococcus aureus Abscess Communities Induce Bone Marrow Cells to Expand into Myeloid-Derived Suppressor Cells

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1446
Author(s):  
Marloes I. Hofstee ◽  
Anja Heider ◽  
Sonja Häckel ◽  
Caroline Constant ◽  
Martijn Riool ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Numbers ◽  
Biomarker Analysis ◽  
Marrow Cells

Staphylococcus aureus is the main causative pathogen of subcutaneous, bone, and implant-related infections, forming structures known as staphylococcal abscess communities (SACs) within tissues that also contain immunosuppressive myeloid-derived suppressor cells (MDSCs). Although both SACs and MDSCs are present in chronic S. aureus infections, it remains unknown whether SACs directly trigger MDSC expansion. To investigate this, a previously developed 3D in vitro SAC model was co-cultured with murine and human bone marrow cells. Subsequently, it was shown that SAC-exposed human CD11blow/− myeloid cells or SAC-exposed murine CD11b+ Gr-1+ cells were immunosuppressive mainly by reducing absolute CD4+ and CD8α+ T cell numbers, as shown in T cell proliferation assays and with flow cytometry. Monocytic MDSCs from mice with an S. aureus bone infection also strongly reduced CD4+ and CD8α+ T cell numbers. Using protein biomarker analysis and an immunoassay, we detected in SAC–bone marrow co-cultures high levels of GM-CSF, IL-6, VEGF, IL-1β, TNFα, IL-10, and TGF-β. Furthermore, SAC-exposed neutrophils expressed Arg-1 and SAC-exposed monocytes expressed Arg-1 and iNOS, as shown via immunofluorescent stains. Overall, this study showed that SACs cause MDSC expansion from bone marrow cells and identified possible mediators to target as an additional strategy for treating chronic S. aureus infections.

scholarly journals Myeloid-Derived Suppressor Cells Regulate Growth of Multiple Myeloma by Inhibiting T Cells in Bone Marrow

2013 ◽  
Vol 190 (7) ◽  
pp. 3815-3823 ◽  
Author(s):  
Indu R. Ramachandran ◽  
Anna Martner ◽  
Alexandra Pisklakova ◽  
Thomas Condamine ◽  
Tess Chase ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Bendamustine with Total Body Irradiation Limits Murine Graft-Versus-Host Disease in Part Via Myeloid-Derived Suppressor Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2040-2040 ◽  
Author(s):  
Emely Hoffman ◽  
Jessica Stokes ◽  
Megan Stanley Molina ◽  
Emmanuel Katsanis
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Total Body Irradiation ◽  
Conditioning Regimen ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Myeloablative Conditioning ◽  
Graft Versus Host ◽  
Total Body

Abstract Background GvHD remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An under-investigated strategy to reduce GvHD is the modification of the preparative conditioning regimen. Cyclophosphamide (CY) and total body irradiation (TBI) is a commonly utilized myeloablative conditioning regimen, but is associated with GvHD. Bendamustine (BEN) is an alkylating agent that has been applied recently in nonmyeloablative chemotherapy-based conditioning regimens, demonstrating reduced myelosuppression, transplant related mortality, and acute graft versus host disease (GvHD). We have recently published that BEN can effectively replace CY when given following murine haploidentical bone marrow transplantation. We therefore hypothesized that BEN can also have advantages over CY when given in conjunction with TBI as a myeloablative preparative regimen. Methods We used a major histocompatibility mismatched murine BMT model to evaluate GvHD following BEN-TBI and CY-TBI conditioning. BALB/c (H-2d) mice received equivalent doses of BEN or CY (based on maximum tolerated dose), followed by TBI (400 cGy) and infusion of bone marrow (BM) cells with splenocytes (SC) or purified T-cells from C57BL/6 (H-2b) mice. GvHD morbidity and mortality and engraftment were monitored and MDSC frequencies were assessed by flow cytometry and immunofluorescence. Results We demonstrate that BEN-TBI conditioning, while facilitating complete donor chimerism, results in significantly less GvHD and improved survival compared to CY-TBI. In BEN-TBI conditioned mice, suppressive CD11b+Gr-1high myeloid cells are increased in the blood, bone marrow (BM), and spleen, with no evident differences in suppressive function. The ratio of Gr-1+ cells to T-cells is significantly increased in BEN-TBI mice in the intestines. When Gr-1high cells are depleted prior to transplant, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of G-CSF, which promotes CD11b+Gr-1+ myeloid cell expansion, trends towards an increase in survival in BEN-TBI mice. Conclusions These findings indicate a potential role of granulocytic myeloid-derived suppressor cells (MDSCs) in the mechanism by which BEN allows engraftment with reduced GvHD. BEN-TBI conditioning reduces GvHD morbidity and mortality compared to CY-TBI and may present a safer alternative to CY-TBI as a myeloablative conditioning regimen in allogeneic HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Murine Staphylococcus aureus chronic infection is cured by theory-driven therapy

2020 ◽  
Author(s):  
Lito A. Papaxenopoulou ◽  
Gang Zhao ◽  
Sahamoddin Khailaie ◽  
Konstantinos Katsoulis-Dimitriou ◽  
Ingo Schmitz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Chronic Infection ◽  
Suppressor Cells ◽  
Therapeutic Strategies ◽  
Infection Model ◽  
Myeloid Derived Suppressor Cells ◽  
Recurrent Infections ◽  
Human Pathogen ◽  
Chronic Infections ◽  
Model Driven

AbstractStaphylococcus aureus (S. aureus) is a challenging human pathogen due to its ability to evade the immune system and resist multidrug antibiotics. These evasive strategies lead to chronic and recurrent infections. Many studies have documented that during chronic infections Myeloid Derived Suppressor Cells (MDSCs) exert immunosuppressive mechanisms on T cells. A mathematical model explains how the steady state of chronic infection can be disturbed and suggests therapeutic strategies to clear the infection. Model-driven suggestions were tested experimentally and confirmed complete clearance of S. aureus chronic infection.

scholarly journals Sirt1 Expression Related with Sarcoma Growth after Stem Cell Transplantation Combined with Depletion of Myeloid-Derived Suppressor Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5796-5796
Author(s):  
Ming Li ◽  
Ming Shi ◽  
Yunze Cui ◽  
Yasushi Adachi ◽  
Susumu Ikehara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Malignant Tumors ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Sirt1 Expression ◽  
Cell Transplants ◽  
The Relationship

Abstract Sirtuins (Sirt) play a number of roles in various aging-related diseases such as obesity, diabetes and cancer, and Sirt1 plays a double role in cancer. The combination of bone marrow transplantation (BMT) and thymus transplantation (TT) has been shown to prevent the growth of malignant tumors. Myeloid-derived suppressor cells (MDSCs) can differentiate from bone marrow stem cells under pathological conditions such as cancer, and prevent the potent action of T cells and NK cells, thereby promoting tumor growth. Thus, depleting MDSCs is important when treating cancer. We therefore investigated the relationship between Sirt1 expression and sarcoma growth in sarcoma-bearing mice treated with BMT+TT and the depletion of MDSCs using Gr-1 Ab. Our results showed that only granulocytic MDSCs (G-MDSCs) were depleted by the Gr-1 Ab in these mice. Moreover, the sarcomas decreased significantly in size in the Gr-1 antibody group when compared with the BMT group. This was due to the increase in the percentage of T cells and decrease in the percentage of G-MDSCs. Furthermore, Sirt1 expression decreased significantly in the sarcoma. These findings suggest that inactive Sirt1 may prevent sarcoma growth in sarcoma-bearing mice that receive stem cell transplants and depletion of MDSCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Monocytic myeloid-derived suppressor cells generated from rhesus macaque bone marrow enrich for regulatory T cells

2018 ◽  
Vol 329 ◽  
pp. 50-55 ◽  
Author(s):  
Alan F. Zahorchak ◽  
Angelica Perez-Gutierrez ◽  
Mohamed B. Ezzelarab ◽  
Angus W. Thomson
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Rhesus Macaque ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

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