Browsing by Keyword "Immunomodulation"
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Publication Biodistribution and efficacy of human adipose-Derived Mesenchymal stem cells Following intranodal administration in experimental colitis(Frontiers Media, 2017) Lopez-Santalla, Mercedes; Mancheno-Corvo, Pablo; Escolano, Amelia; Menta, Ramon; DelaRosa, Olga; Luis Abad, Jose; Buscher, Dirk; Redondo, Juan Miguel; Bueren, Juan A.; Dalemans, Wilfried; Lombardo, Eleuterio; Garin, Marina I.; European CommissionMesenchymal stem cells (MSCs) have a large potential in cell therapy for treatment of inflammatory and autoimmune diseases, thanks to their immunomodulatory properties. The encouraging results in animal models have initiated the translation of MSC therapy to clinical trials. In cell therapy protocols with MSCs, administered intravenously, several studies have shown that a small proportion of infused MSCs can traffic to the draining lymph nodes (LNs). This is accompanied with an increase of different types of regulatory immune cells in the LNs, suggesting the importance of migration of MSCs to the LNs in order to contribute to immunomodulatory response. Intranodal (IN), also referred as intralymphatic, injection of cells, like dendritic cells, is being proposed in the clinic for the treatment of cancer and allergy, showing that this route of administration is clinically safe and efficient. In this study, we investigated, for the first time, the biodistribution and the efficacy of Luciferase+adipose-derived MSCs (Luci-eASCs), infused through the inguinal LNs (iLNs), in normal mice and in inflamed mice with colitis. Most of the LucieASCs remain in the iLNs and in the adipose tissue surrounding the inguinal LNs. A small proportion of Luci-eASCs can migrate to other locations within the lymphatic system and to other tissues and organs, having a preferential migration toward the intestine in colitic mice. Our results show that the infused Luci-eASCs protected 58\% of the mice against induced colitis. Importantly, a correlation between the response to eASC treatment and a higher accumulation of eASCs in popliteal, parathymic, parathyroid, and mesenteric LNs were found. Altogether, these results suggest that IN administration of eASCs is feasible and may represent an effective strategy for cell therapy protocols with human adipose-derived MSCs in the clinic for the treatment of immune-mediated disorders.Publication Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy(Multidisciplinary Digital Publishing Institute (MDPI), 2020-08) Pérez-Romero, Karim; Rodriguez, Ramon M; Amedei, Amedeo; Barcelo-Coblijn, Gwendolyn; Lopez, Daniel HIntegration of the tumor microenvironment as a fundamental part of the tumorigenic process has undoubtedly revolutionized our understanding of cancer biology. Increasing evidence indicates that neoplastic cells establish a dependency relationship with normal resident cells in the affected tissue and, furthermore, develop the ability to recruit new accessory cells that aid tumor development. In addition to normal stromal and tumor cells, this tumor ecosystem includes an infiltrated immune component that establishes complex interactions that have a critical effect during the natural history of the tumor. The process by which immune cells modulate tumor progression is known as immunoediting, a dynamic process that creates a selective pressure that finally leads to the generation of immune-resistant cells and the inability of the immune system to eradicate the tumor. In this context, the cellular and functional characterization of the immune compartment within the tumor microenvironment will help to understand tumor progression and, ultimately, will serve to create novel prognostic tools and improve patient stratification for cancer treatment. Here we review the impact of the immune system on tumor development, focusing particularly on its clinical implications and the current technologies used to analyze immune cell diversity within the tumor.Publication Inflammation, a common mechanism in frailty and COVID-19, and stem cells as a therapeutic approach(AlphaMed Press, Inc., 2021-08-03) Becerra, José; Duran, Ivan; [Becerra,J; Duran,I] Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Málaga, IBIMA, Málaga, Spain. [Becerra,J; Duran,I] Networking Biomedical Research Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain.As our life expectancy increases, specific medical conditions appear, and new challenges are met in terms of global health. Frailty has become a medical and scientific concept to define pathologies where inflammation, depressed immune system, cellular senescence, and molecular aging converge. But more importantly, frailty is the ultimate cause of death that limits our life span and deteriorates health in an increasing proportion of the world population. The difficulty of tackling this problem is the combination of factors that influence frailty appearance, such as stem cells exhaustion, inflammation, loss of regeneration capability, and impaired immunomodulation. To date, multiple research fields have found mechanisms participating in this health condition, but to make progress, science will need to investigate frailty with an interdisciplinary approach. This article summarizes the current efforts to understand frailty from their processes mediated by inflammation, aging, and stem cells to provide a new perspective that unifies the efforts in producing advanced therapies against medical conditions in the context of frailty. We believe this approach against frailty is particularly relevant to COVID-19, since people in a state of frailty die more frequently due to the hyperinflammatory process associated with this infection.Publication Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis(Frontiers Media, 2017-04-21) Mancheño-Corvo, Pablo; Lopez-Santalla, Mercedes; Menta, Ramon; DelaRosa, Olga; Mulero, Francisca; Del Rio, Borja; Ramirez, Cristina; Büscher, Dirk; Bueren, Juan A; Lopez-Belmonte, Juan; Dalemans, Wilfried; Garin, Marina I; Lombardo, Eleuterio; Ministerio de Ciencia y Competitividad (España); Comunidad de Madrid (España); Unión Europea. Comisión Europea. 7 Programa MarcoMesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulatory properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Previous studies have demonstrated that MSCs, administered systemically, migrate to lymphoid tissues associated with the inflammatory site where functional MSC-induced immune cells with a regulatory phenotype were increased mediating the immunomodulatory effects of MSCs. These results suggest that homing of MSCs to the lymphatic system plays an important role in the mechanism of action of MSCs in vivo. Thus, we hypothesized that direct intralymphatic (IL) (also referred as intranodal) administration of MSCs could be an alternative and effective route of administration for MSC-based therapy. Here, we report the feasibility and efficacy of the IL administration of human expanded adipose mesenchymal stem cells (eASCs) in a mouse model of collagen-induced arthritis (CIA). IL administration of eASCs attenuated the severity and progression of arthritis, reduced bone destruction and increased the levels of regulatory T cells (CD25+Foxp3+CD4+ cells) and Tr1 cells (IL10+CD4+), in spleen and draining lymph nodes. Taken together, these results indicate that IL administration of eASCs is very effective in modulating established CIA and may represent an alternative treatment modality for cell therapy with eASCs.Publication It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug(Frontiers Media, 2012) Mesa-Arango, Ana Cecilia; Scorzoni, Liliana; Zaragoza, Oscar; Fundación Carolina; Agencia Española de Cooperación Internacional para el Desarrollo; Ministerio de Economía y Competitividad (España)"Amphotericin B acts through pore formation at the cell membrane after binding to ergosterol" is an accepted dogma about the action mechanism of this antifungal, and this sentence is widely found in the literature. But after 60 years of investigation, the action mechanism of Amphotericin B is not fully elucidated. Amphotericin B is a polyene substance that is one of the most effective drugs for the treatment of fungal and parasite infections. As stated above, the first mechanism of action described was pore formation after binding to the ergosterol present in the membrane. But it has also been demonstrated that AmB induces oxidative damage in the cells. Moreover, amphotericin B modulates the immune system, and this activity has been related to the protective effect of the molecule, but also to its toxicity in the host. This review tries to provide a general overview of the main aspects of this molecule, and highlight the multiple effects that this molecule has on both the fungal and host cells.Publication Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis(BioMed Central (BMC), 2016-03-17) Bravo, Beatriz; Gallego, Marta Ines; Flores, Ana I; Bornstein, Rafael; Puente-Bedia, Alba; Hernandez, Javier R; de la Torre, Paz; Garcia-Zaragoza, Elena; Perez-Tavarez, Raquel; Grande, Jesús; Ballester, Alicia; Ballester, SaraBACKGROUND: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. METHODS: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. RESULTS: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4(+)IL17(+), CD11b(+)Ly6G(+) and CD11b(+)Ly6C(+) cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. CONCLUSIONS: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.Publication Rodent Models for the Study of Soil-Transmitted Helminths: A Proteomics Approach.(Frontiers Media, 2021-04-22) Montaño, Karen J; Cuéllar, Carmen; Sotillo, Javier; Instituto de Salud Carlos III; Unión Europea. Comisión EuropeaSoil-transmitted helminths (STH) affect hundreds of millions worldwide and are some of the most important neglected tropical diseases in terms of morbidity. Due to the difficulty in studying STH human infections, rodent models have become increasingly used, mainly because of their similarities in life cycle. Ascaris suum and Trichuris muris have been proven appropriate and low maintenance models for the study of ascariasis and trichuriasis. In the case of hookworms, despite most of the murine models do not fully reproduce the life cycle of Necator americanus, their proteomic similarity makes them highly suitable for the development of novel vaccine candidates and for the study of hookworm biological features. Furthermore, these models have been helpful in elucidating some basic aspects of our immune system, and are currently being used by numerous researchers to develop novel molecules with immunomodulatory proteins. Herein we review the similarities in the proteomic composition between Nippostrongylus brasiliensis, Heligmosomoides polygyrus bakeri and Trichuris muris and their respective human counterpart with a focus on the vaccine candidates and immunomodulatory proteins being currently studied.Publication The immunomodulatory activity of extracellular vesicles derived from endometrial mesenchymal stem cells on CD4+ T cells is partially mediated by TGFbeta(2018-10) Alvarez, Veronica; Sánchez-Margallo, Francisco Miguel; Macías-García, Beatriz; Gomez-Serrano, Maria; Jorge, Inmaculada; Vazquez, Jesus; Blázquez, Rebeca; Casado, Javier G; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Government of Extremadura (España); Ministerio de Economía, Industria y Competitividad (España); Fundación La Marató TV3; Ministerio de Ciencia, Innovación y Universidades (España); Fundación ProCNICEndometrial mesenchymal stem cells (endMSCs) reside in the basal and functional layer of human endometrium and participate in tissue remodelling, which is required for maintaining the regenerative capacity of the endometrium. The endMSCs are multipotent stem cells and exhibit immunomodulatory effects. This paper aimed to evaluate the regulatory effects of extracellular vesicles derived from endMSCs (EV-endMSCs) in the setting of T cell activation. In vitro stimulations of lymphocytes were performed in the presence of EV-endMSCs. These in vitro-stimulated lymphocytes were functionally and phenotypically characterized to distinguish CD4+ and CD8+ T cell differentiation subsets. Moreover, the inhibition of TGFβ was performed with neutralizing antibodies. The phenotype and nanoparticle tracking analysis of the EV-endMSCs demonstrated that they are similar in terms of size distribution to other mesenchymal stem cells-derived exosomes. The in vitro assays showed an immunomodulatory potential of these vesicles to counteract the differentiation of CD4+ T cells. The quantification of active TGFβ in EV-endMSCs was found to be very high when compared with extracellular vesicles-free concentrated supernatants. Finally, the neutralization of TGFβ significantly attenuated the immunomodulatory activity of EV-endMSCs. In summary, this is the first report demonstrating that EV-endMSCs exhibit a potent inhibitory effect against CD4+ T cell activation, which is partially mediated by TGFβ signalling.Publication Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence(Impact Journals, 2015) Niu, Ping; Smagul, Aibek; Wang, Lu; Sadvakas, Aiman; Sha, Ying; Perez, Laura M.; Nussupbekova, Aliya; Amirbekov, Aday; Akanov, Akan A.; Galvez, Beatriz G.; Jordan, I. King; Lunyak, Victoria V.; Ministerio de Ciencia e Innovación (España)Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and antiapoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.Publication Tyrosine kinase inhibitors: potential use and safety considerations in HIV-1 infection(Taylor & Francis, 2017-05) Coiras, Mayte; Ambrosioni, Juan; Cervantes, Francisco; Miró, José M; Alcamí, José; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Red de Investigación Cooperativa en Investigación en Sida (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)INTRODUCTION: Infection caused by HIV-1 is nowadays a chronic disease due to a highly efficient antiretroviral treatment that is nevertheless, unable to eliminate the virus from the organism. New strategies are necessary in order to impede the formation of the viral reservoirs, responsible for the failure of the antiretroviral treatment to cure the infection. Areas covered: The purpose of this review is to discuss the possibility of using tyrosine kinase inhibitors (TKIs) for the treatment of HIV-1 infection. These inhibitors are successfully used in patients with distinct cancers such as chronic myeloid leukemia. The most relevant papers have been selected and commented. Expert opinion: The family of TKIs are directed against the activation of tyrosine kinases from the Src family. Some of these kinases are essential for the activation of CD4 + T cells, the major target of HIV-1. During acute or primary infection the CD4 + T cells are massively activated, which is mostly responsible for the generation of the reservoirs, the spread of the infection and the destruction of activated CD4 + T cells, infected or not. Consequently, we discuss the possibility of using TKIs as adjuvant of the antiretroviral treatment against HIV-1 infection mostly, but not exclusively, during the acute/recent phase.