scholarly journals Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of regulatory T lymphocytes in vitro and in vivo

2010 ◽  
Vol 129 (2) ◽  
pp. 374-386 ◽  
Author(s):  
Natalia Suarez ◽  
Carlos Alfaro ◽  
Juan Dubrot ◽  
Asis Palazon ◽  
Elixabet Bolaños ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Synergistic Effects ◽  
Regulatory T Lymphocytes

scholarly journals Multiple sclerosis-associated changes in the composition and immune functions of spore-forming bacteria

2018 ◽  
Author(s):  
Egle Cekanaviciute ◽  
Anne-Katrin Pröbstel ◽  
Anna Thomann ◽  
Tessel F. Runia ◽  
Patrizia Casaccia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
Microbial Communities ◽  
Immune Functions ◽  
Simple Description ◽  
Regulatory T Lymphocytes ◽  
Select Group ◽  
Spore Forming Bacteria

AbstractMultiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa and show that their presence correlates with impaired differentiation of IL-10 secreting, regulatory T lymphocytes in-vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of pro-inflammatory, IFNγ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control derived spore-forming bacteria were able to induce immunoregulatory responses.Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth.ImportanceDespite the rapid emergence of microbiome related studies in human diseases, few go beyond a simple description of relative taxa levels in a select group of patients. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of both complete microbial communities and individual taxa, revealing novel functional associations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is associated with impaired immunomodulatory responses in vitro.

Absence of CCR4 Enhances the Function of Expanded Regulatory T-Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2172-2172
Author(s):  
James M. Coghill ◽  
Hans Seidel ◽  
Jonathan S. Serody
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Critical Role ◽  
Cell Transplant ◽  
Similar Frequency ◽  
Regulatory T Lymphocytes ◽  
Treg Function

Abstract Chemokine Receptor 4 (CCR4) has been shown to be important for the homing of effector T-lymphocytes (Teffs) to cutaneous and possibly pulmonary sites of inflammation. CCR4 is also expressed on the surface of regulatory T-lymphocytes (Tregs), and previous work has suggested a critical role for CCR4 for their in-vivo suppressive ability. Since the skin and lung are important sites of graft-versus-host disease (GVHD) morbidity, we set out to determine the contribution of CCR4 to both Teff and Treg function in a murine stem-cell transplant model. Methods: C57BL/6 (B6) mice served as bone marrow (BM) donors, and B6xDBA/2 F1 (B6D2) mice functioned as recipients. Teffs and Tregs were obtained from wild-type (WT) or CCR4 knockout (CCR4−/−) B6 mice. For Teff studies, recipient animals were lethally irradiated and administered T-cell depleted (TCD) BM cells +/− splenic Teffs from WT or CCR4−/− donors. For Treg studies, mice received TCD BM + WT Teffs +/− naive or expanded Tregs from WT or CCR4−/− donors. Results: Animals receiving WT or CCR4−/− Teffs all developed severe GVHD with an 88% mortality rate. Using flow cytometry, we demonstrated that WT and CCR4−/− eGFP+ Teffs were able to accumulate in the skin and lungs of recipient animals at a similar frequency, suggesting a non-essential role for CCR4 in Teff homing to these sites. Attention was next directed towards the influence of CCR4 on Treg function in-vivo. Those animals receiving BM and Teffs without Tregs developed aggressive GVHD with 100% mortality. In contrast, when animals were administered BM and naïve Tregs from either WT or CCR4−/− donors two days prior to receiving Teffs, all animals demonstrated 100% survival and only mild GVHD, suggesting a non-obligatory role for CCR4 for Treg function in-vivo. Since CCR4 is upregulated on Tregs and Teffs after activation, we next examined whether its absence would exert a greater effect on the ability of expanded Tregs to protect against GVHD in-vivo compared to naïve cells. Animals were irradiated and received TCD BM plus Teffs +/− Tregs from WT or CCR4−/− donors previously expanded in-vitro. Those animals receiving BM and Teffs without Tregs all developed severe GVHD with 100% mortality. Ex-vivo expanded WT Tregs, 80% of which expressed L-selectin at low levels, provided only marginal GVHD protection with 12.5% survival when given concurrently with Teffs at a 1:1 ratio. In contrast, expanded CCR4−/− Tregs provided superior in-vivo GVHD protection, with 50% of mice surviving long term (see figure, p=.05 for WT versus CCR4−/− Treg groups). This enhanced protection in-vivo occurred despite an inferior ability of expanded CCR4−/− Tregs to inhibit T-cell proliferation in an in-vitro mixed lymphocyte reaction compared to WT cells. Migration studies did not reveal a difference in the trafficking of expanded CCR4−/− Tregs compared to WT cells except for a greater frequency of CCR4−/− Tregs in the mesenteric lymph node on day +7. Conclusions: Our data suggest that naïve CCR4−/− Tregs are as efficient as WT cells in preventing GVHD, and that CCR4 is not required for the induction of GVHD by Teffs. Paradoxically we show that expanded Tregs function better to prevent GVHD in the absence of CCR4. Current work is underway to determine the mechanism for this finding. Figure Figure

scholarly journals Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4216-4221 ◽  
Author(s):  
Olivier Joffre ◽  
Nathalie Gorsse ◽  
Paola Romagnoli ◽  
Denis Hudrisier ◽  
Joost P. M. van Meerwijk
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Third Party ◽  
Antigen Specificity ◽  
Minor Histocompatibility Antigens ◽  
Regulatory T Lymphocytes

Abstract Thymus-derived regulatory T lymphocytes of CD4+CD25+ phenotype regulate a large variety of beneficial and deleterious immune responses and can inhibit lethal graft-versus-host disease in rodents. In vitro, CD4+CD25+ T cells require specific major histocompatibility complex (MHC)/peptide ligands for their activation, but once activated they act in an antigen-nonspecific manner. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen specificity of their suppressor-effector function. Here we show that CD4+CD25+ regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic antigen-presenting cells (APCs) induced specific long-term tolerance to bone marrow grafts disparate for major and minor histocompatibility antigens; whereas “target” bone marrow was protected, third-party bone marrow was rejected. Importantly, in mice injected with a mix of target and third-party bone marrows, protection and rejection processes took place simultaneously. These results indicate that CD4+CD25+ regulatory T cells can act in an antigen-specific manner in vivo. Our results suggest that CD4+CD25+ regulatory T cells could in the future be used in clinical settings to induce specific immunosuppression. (Blood. 2004;103:4216-4221)

Recent Patents on Anti-Cancer Potential of Helenalin

2020 ◽  
Vol 15 (2) ◽  
pp. 132-142
Author(s):  
Priyanka Kriplani ◽  
Kumar Guarve
Keyword(s):  
Synergistic Effects ◽  
Therapeutic Interventions ◽  
Active Constituent ◽  
Scientific Impact ◽  
Isolation Techniques ◽  
Anti Cancer ◽  
Prevention Of Cancer ◽  
Synthetic Derivatives

Background: Arnica montana, containing helenalin as its principal active constituent, is the most widely used plant to treat various ailments. Recent studies indicate that Arnica and helenalin provide significant health benefits, including anti-inflammatory, neuroprotective, antioxidant, cholesterol-lowering, immunomodulatory, and most important, anti-cancer properties. Objective: The objective of the present study is to overview the recent patents of Arnica and its principal constituent helenalin, including new methods of isolation, and their use in the prevention of cancer and other ailments. Methods: Current prose and patents emphasizing the anti-cancer potential of helenalin and Arnica, incorporated as anti-inflammary agents in anti-cancer preparations, have been identified and reviewed with particular emphasis on their scientific impact and novelty. Results: Helenalin has shown its anti-cancer potential to treat multiple types of tumors, both in vitro and in vivo. It has also portrayed synergistic effects when given in combination with other anti- cancer drugs or natural compounds. New purification/isolation techniques are also developing with novel helenalin formulations and its synthetic derivatives have been developed to increase its solubility and bioavailability. Conclusion: The promising anti-cancer potential of helenalin in various preclinical studies may open new avenues for therapeutic interventions in different tumors. Thus clinical trials validating its tumor suppressing and chemopreventive activities, particularly in conjunction with standard therapies, are immediately required.

scholarly journals DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Elisa Izquierdo ◽  
Diana Carvalho ◽  
Alan Mackay ◽  
Sara Temelso ◽  
Jessica K R Boult ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Mesenchymal Transition

Abstract The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

scholarly journals Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2204
Author(s):  
Meng-Die Yang ◽  
Yang Sun ◽  
Wen-Jun Zhou ◽  
Xiao-Zheng Xie ◽  
Qian-Mei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Viability ◽  
Synergistic Effects ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

scholarly journals Design of a multi-epitope vaccine against cervical cancer using immunoinformatics approaches

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samira Sanami ◽  
Fatemeh Azadegan-Dehkordi ◽  
Mahmoud Rafieian-Kopaei ◽  
Majid Salehi ◽  
Maryam Ghasemi-Dehnoo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Lymphocytes ◽  
Tertiary Structure ◽  
Therapeutic Vaccine ◽  
Epitope Prediction ◽  
Therapeutic Effects ◽  
Epitope Vaccine ◽  
In Vivo Experiments

AbstractCervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.

Tocotrienols and Cancer: From the State of the Art to Promising Novel Patents

2019 ◽  
Vol 14 (1) ◽  
pp. 5-18 ◽  
Author(s):  
Fabrizio Fontana ◽  
Michela Raimondi ◽  
Monica Marzagalli ◽  
Roberta M. Moretti ◽  
Marina Montagnani Marelli ◽  
...  
Keyword(s):  
Cancer Prevention ◽  
State Of The Art ◽  
Synergistic Effects ◽  
The State ◽  
Therapeutic Interventions ◽  
Multiple Tumor ◽  
Anti Cancer ◽  
Important Health

Background: Tocotrienols (TTs) are vitamin E derivatives naturally occurring in several plants and vegetable oils. Like Tocopherols (TPs), they comprise four isoforms, α, β, γ and δ, but unlike TPs, they present an unsaturated isoprenoid chain. Recent studies indicate that TTs provide important health benefits, including neuroprotective, anti-inflammatory, anti-oxidant, cholesterol lowering and immunomodulatory effects. Moreover, they have been found to possess unique anti-cancer properties.Objective:The purpose of this review is to present an overview of the state of the art of TTs role in cancer prevention and treatment, as well as to describe recent patents proposing new methods for TTs isolation, chemical modification and use in cancer prevention and/or therapy.Methods:Recent literature and patents focusing on TTs anti-cancer applications have been identified and reviewed, with special regard to their scientific impact and novelty.Results:TTs have demonstrated significant anti-cancer activity in multiple tumor types, both in vitro and in vivo. Furthermore, they have shown synergistic effects when given in combination with standard anti-cancer agents or other anti-tumor natural compounds. Finally, new purification processes and transgenic sources have been designed in order to improve TTs production, and novel TTs formulations and synthetic derivatives have been developed to enhance their solubility and bioavailability.Conclusion:The promising anti-cancer effects shown by TTs in several preclinical studies may open new opportunities for therapeutic interventions in different tumors. Thus, clinical trials aimed at confirming TTs chemopreventive and tumor-suppressing activity, particularly in combination with standard therapies, are urgently needed.

scholarly journals Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0136885 ◽  
Author(s):  
Stéphane Kerbrat ◽  
Benoit Vingert ◽  
Marie-Pierre Junier ◽  
Flavia Castellano ◽  
François Renault-Mihara ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Adaptor Protein

Investigation of synergistic effects of inductive and conductive factors in gelatin-based cryogels for bone tissue engineering

2016 ◽  
Vol 4 (10) ◽  
pp. 1827-1841 ◽  
Author(s):  
Han-Tsung Liao ◽  
K. T. Shalumon ◽  
Kun-Hung Chang ◽  
Chialin Sheu ◽  
Jyh-Ping Chen
Keyword(s):  
Tissue Engineering ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Synergistic Effects

Gelatin cryogels modified with nHAP and BMP-2 could provide cues to promote the osteogenesis of ADSCs in vitro and in vivo.

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