31 results on '"Cecilia Muñoz-Calleja"'
Search Results
2. Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors
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Silvia Santamaria, Marisa Delgado, Marta Botas, Eva Castellano, Isabel Corraliza-Gorjon, Paloma Lafuente, Cecilia Muñoz-Calleja, Maria L. Toribio, Leonor Kremer, Jose A. Garcia-Sanz, Instituto de Salud Carlos III, European Commission, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), Santamaría, Silvia, Delgado, Marisa, Botas, Marta, Castellano, Eva, Corraliza-Gorjon, Isabel, Lafuente, Paloma, Muñoz-Calleja, Cecilia, Toribio, María Luisa, Kremer, Leonor, García-Sanz, José A., Santamaría, Silvia [0000-0003-2100-2657], Delgado, Marisa [0000-0002-6446-3237], Botas, Marta [0000-0002-1639-7220], Castellano, Eva [0000-0003-0858-914X], Corraliza-Gorjon, Isabel [0000-0002-0054-7511], Lafuente, Paloma [0000-0001-8617-5992], Muñoz-Calleja, Cecilia [0000-0003-4085-3115], Toribio, María Luisa [0000-0002-8637-0373], Kremer, Leonor [0000-0002-2235-2010], and García-Sanz, José A. [0000-0002-1153-6025]
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Combined chemotherapy and immunotherapy ,Therapeutic antibodies ,Immunology ,Antitumoral activity ,CCR9 positive T-ALL leukemia ,Orthotopic xenograft mouse model ,Adenocarcinoma ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Pancreatic Neoplasms ,Mice ,Receptors, CCR ,Animals ,Heterografts ,Humans ,Immunology and Allergy ,T-ALL leukemia ,Chemokine receptor CCR9 - Abstract
18 p.-7 fig.-2 tab., Relapsed or refractory T acute lymphoblastic leukemia (T-ALL) still carries poor prognosis. Aiming to improve outcomes, the therapeutic potential of an anti-CCR9 monoclonal antibody (mAb 92R), targeting the human chemokine-receptor CCR9 is analyzed on orthotopic xenotransplants. 92R mAb treatment of mice carrying human CCR9+ T-ALL cell lines or primary T cell leukemias inhibits tumor growth and increases survival. The therapeutic effects of 92R are specific and synergize with chemotherapeutic agents increasing survival. Furthermore, 92R decreases size of non-hematopoietic tumors with a forced CCR9 expression and of solid tumors generated by the pancreatic adenocarcinoma cell line AsPC-1. In addition, a humanized version of 92R mAb (Srb1) is also able to inhibit growth of CCR9+ T-ALL tumor cells in vivo, increasing survival 2.66-fold. Finally, 92R mAb prevents liver accumulation of infiltrates and reduces tumor cell numbers in already formed infiltrates. Thus, the humanized version of 92R mAb (Srb1), displays therapeutic potential for CCR9+ tumor treatment and might represent one of the first therapeutic antibodies for precision medicine on T-ALL patients., The work in the author’s laboratories was partially supported by grants from the PN2014-A from the ISCIII (PI14/00703, co-financed by FEDER funds from the EU, Operative program on Intelligent Growth 2014-2020, to LK); the Spanish Ministry of Economy, Industry and Competitiveness (RTC-2015-3786-1 to LK and JG-S), co-financed by FEDER funds from the EU and from the Spanish Ministry of Science and Innovation (PID2019-105404RB-I00 to JAGS and LK financed by MCIN/AEI/10.13039/501100011033). As well as the CSIC (PIE-201420E109 and PIE-201720E092, to LK).
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- 2022
3. COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes
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Hortensia de la Fuente, Pedro Martínez-Fleta, Ignacio Santos, Ana Alcaraz-Serna, Elena Ávalos, Ana Marcos-Jimenez, Arantzazu Alfranca, Beatriz Aldave, Ana Sanchez-Azofra, Ildefonso Sánchez-Cerrillo, Isidoro González-Álvaro, Luciana del Campo Guerola, Tamara Mateu-Albero, Pedro Landete, Maria J. Calzada, Santiago Sánchez-Alonso, Francisco Sánchez-Madrid, Enrique Martín-Gayo, Ligia Gabrie, Laura Esparcia, Joan B. Soriano, Celia López-Sanz, Cecilia Muñoz-Calleja, and Julio Ancochea
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0301 basic medicine ,ARDS ,Lung ,Myeloid ,business.industry ,T cell ,Inflammation ,General Medicine ,medicine.disease ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,030220 oncology & carcinogenesis ,Immunology ,medicine ,medicine.symptom ,business ,CD8 - Abstract
SARS-CoV-2 is responsible for the development of coronavirus disease 2019 (COVID-19) in infected individuals, who can either exhibit mild symptoms or progress toward a life-threatening acute respiratory distress syndrome (ARDS). Exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8+ T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. Here, we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood and lung of COVID-19 patients with different clinical severity in comparison with healthy individuals. Furthermore, these subpopulations and their association with antiviral effector CD8+ T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Our results indicate that inflammatory transitional and nonclassical monocytes and CD1c+ conventional dendritic cells preferentially migrate from blood to lungs in patients with severe COVID-19. Thus, this study increases the knowledge of specific myeloid subsets involved in the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies for fighting SARS-CoV-2 infection.
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- 2020
4. A Differential Signature of Circulating miRNAs and Cytokines Between COVID-19 and Community-Acquired Pneumonia Uncovers Novel Physiopathological Mechanisms of COVID-19
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Pedro Martínez-Fleta, Paula Vera-Tomé, María Jiménez-Fernández, Silvia Requena, Emilia Roy-Vallejo, Ancor Sanz-García, Marta Lozano-Prieto, Celia López-Sanz, Alicia Vara, Ángel Lancho-Sánchez, Enrique Martín-Gayo, Cecilia Muñoz-Calleja, Arantzazu Alfranca, Isidoro González-Álvaro, José María Galván-Román, Javier Aspa, Hortensia de la Fuente, and Francisco Sánchez-Madrid
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Male ,community-acquired pneumonia ,Immunology ,COVID-19 ,Pneumonia ,RC581-607 ,Middle Aged ,microRNAs ,Cohort Studies ,Community-Acquired Infections ,Logistic Models ,Cytokines ,Humans ,Immunology and Allergy ,Female ,Circulating MicroRNA ,Immunologic diseases. Allergy ,Biomarkers ,plasma ,soluble proteins ,Original Research - Abstract
Coronavirus Disease 2019 (COVID-19) pneumonia is a life-threatening infectious disease, especially for elderly patients with multiple comorbidities. Despite enormous efforts to understand its underlying etiopathogenic mechanisms, most of them remain elusive. In this study, we compared differential plasma miRNAs and cytokines profiles between COVID-19 and other community-acquired pneumonias (CAP). A first screening and subsequent validation assays in an independent cohort of patients revealed a signature of 15 dysregulated miRNAs between COVID-19 and CAP patients. Additionally, multivariate analysis displayed a combination of 4 miRNAs (miR-106b-5p, miR-221-3p, miR-25-3p and miR-30a-5p) that significantly discriminated between both pathologies. Search for targets of these miRNAs, combined with plasma protein measurements, identified a differential cytokine signature between COVID-19 and CAP that included EGFR, CXCL12 and IL-10. Significant differences were also detected in plasma levels of CXCL12, IL-17, TIMP-2 and IL-21R between mild and severe COVID-19 patients. These findings provide new insights into the etiopathological mechanisms underlying COVID-19.
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- 2022
5. CD4+ T Cell Immune Specificity Changes After Vaccination in Healthy And COVID-19 Convalescent Subjects
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Laura Esparcia-Pinedo, Pedro Martínez-Fleta, Noelia Ropero, Paula Vera-Tomé, Hugh T. Reyburn, José M. Casasnovas, José M. Rodríguez Frade, Mar Valés-Gómez, Carlos Vilches, Enrique Martín-Gayo, Cecilia Muñoz-Calleja, Francisco Sanchez-Madrid, Arantzazu Alfranca, Instituto de Salud Carlos III, European Commission, Cooperativa de Viviendas Buen Suceso, Red de Investigación Cardiovascular (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), La Caixa, Banco Santander, Conferencia de Rectores de las Universidades Españolas, Comunidad de Madrid, and Consejo Superior de Investigaciones Científicas (España)
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Immunology ,Adaptive immunity ,Immunization, Secondary ,T-Cell Antigen Receptor Specificity ,Humans ,Immunology and Allergy ,BNT162 Vaccine ,Cells, Cultured ,Original Research ,SARS-CoV-2 ,Vaccination ,T cell ,COVID-19 ,Convalescence ,adaptive immunity ,immune profile ,RC581-607 ,Middle Aged ,Healthy Volunteers ,Immunoglobulin A ,Immune profile ,Immunoglobulin G ,Spike Glycoprotein, Coronavirus ,Female ,Immunologic diseases. Allergy - Abstract
The immune response promoted by SARS-CoV-2 vaccination is relevant to develop novel vaccines and optimized prevention strategies. We analyzed the adaptive immunity in healthy donors (HD) and convalescent individuals (CD), before and after administering BNT162b2 vaccine. Our results revealed specific changes in CD4+ T cell reactivity profile in vaccinated HD and CD, with an increase in S1 and S2 positive individuals, proportionally higher for S2. On the contrary, NCAP reactivity observed in HD and CD patients was no longer detectable after vaccination. Despite the substantial antibody response in CD, MPro-derived peptides did not elicit CD4+ lymphocyte activation in our assay in either condition. HD presented an increment in anti-S and anti-RBD IgG after first dose vaccination, which increased after the second vaccination. Conversely, anti-S and anti-RBD IgG and IgA titers increased in already positive CD after first dose administration, remaining stable after second dose inoculation. Interestingly, we found a strong significant correlation between S1-induced CD4+ response and anti-S IgA pre-vaccination, which was lost after vaccine administration., This work was supported by grants to AA: FIS PI19/01491 (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional FEDER) and Sociedad Cooperativa de Viviendas Buen Suceso, S.Coop.Mad. To AA and FS-M: CIBER Cardiovascular from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional; FEDER). To FS-M: SAF2017-82886-R (Spanish Ministry of Economy and Competitiveness MINECO)), HR17-00016 (“La Caixa” Banking Foundation), “Fondos Supera COVID19” (Banco de Santander and CRUE), “Ayuda Covid 2019” and “Inmunovacter” REACT-UE (Comunidad de Madrid). To MV: Spanish National Research Council (CSIC, project number 202020E079 and CSIC-COVID19-028).
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- 2022
6. Studies for new applications of a monoclonal antibody antiCCR7. Validation as a therapy in onco-immunology
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Fernando Terrón, Medicinal Products, Madrid, Spain, Immunological Immed S.L., Wim Mol, Raquel Juárez-Sánchez, Carlos Cuesta-Mateos, and Cecilia Muñoz-Calleja
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business.industry ,medicine.drug_class ,Immunology ,Medicine ,business ,Monoclonal antibody - Published
- 2021
7. Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target
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Carlos Cuesta-Mateos, Jennifer R. Brown, Fernando Terrón, and Cecilia Muñoz-Calleja
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lcsh:Immunologic diseases. Allergy ,Receptors, CCR7 ,CLL (chronic lymphocytic leukemia) ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Gene Expression ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 7 ,Review ,Ligands ,Pathogenesis ,Chemokine receptor ,Immune system ,immune system diseases ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Immune Tolerance ,Tumor Microenvironment ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Molecular Targeted Therapy ,Lymph node ,pathophysiology ,B-Lymphocytes ,business.industry ,Chemotaxis ,Immunotherapy ,lymph node ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,medicine.anatomical_structure ,Cancer research ,immunotherapy ,Disease Susceptibility ,Lymph Nodes ,Signal transduction ,lcsh:RC581-607 ,business ,CCR7 ,Protein Binding - Abstract
The lymph node (LN) is an essential tissue for achieving effective immune responses but it is also critical in the pathogenesis of chronic lymphocytic leukemia (CLL). Within the multitude of signaling pathways aberrantly regulated in CLL the homeostatic axis composed by the chemokine receptor CCR7 and its ligands is the main driver for directing immune cells to home into the LN. In this literature review, we address the roles of CCR7 in the pathophysiology of CLL, and how this chemokine receptor is of critical importance to develop more rational and effective therapies for this malignancy.
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- 2021
8. Effect of ibrutinib on CCR7 expression and functionality in chronic lymphocytic leukemia and its implication for the activity of CAP-100, a novel therapeutic anti-CCR7 antibody
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Carlos Cuesta-Mateos, Javier Loscertales, Raquel Juárez-Sánchez, Fernando Terrón, Tamara Mateu-Albero, Cecilia Muñoz-Calleja, and Wim Mol
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Cancer Research ,Receptors, CCR7 ,Combination therapy ,medicine.drug_class ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,C-C chemokine receptor type 7 ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,Chemokine receptor ,Antineoplastic Agents, Immunological ,Piperidines ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,Immunology and Allergy ,Medicine ,Humans ,Protein Kinase Inhibitors ,Dose-Response Relationship, Drug ,business.industry ,Adenine ,Antibody-Dependent Cell Cytotoxicity ,Membrane Proteins ,Immunotherapy ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Gene Expression Regulation, Neoplastic ,Cell killing ,Oncology ,chemistry ,Ibrutinib ,Cancer research ,business - Abstract
CAP-100 is a novel therapeutic antibody directed against the ligand binding site of human CCR7. This chemokine receptor is overexpressed in chronic lymphocytic leukemia (CLL) and orchestrates the homing of CLL cells into the lymph node. Previous studies, on a very limited number of samples, hypothesized that the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib might induce loss of surface CCR7 levels in CLL cells. CAP-100 will be evaluated in clinical trials as a therapy for relapse/refractory CLL patients, who have received at least two systemic therapies (NCT04704323). As nowadays many relapse/refractory CLL patients will have received ibrutinib as a prior therapy, we aimed to investigate in a large cohort of CLL patients the impact of this BTKi on CCR7 expression and functionality as well as on the therapeutic activity of CAP-100. Our data confirm that ibrutinib moderately down-regulates the very high expression of CCR7 in CLL cells but has no apparent effect on CCR7-induced chemotaxis. Moreover, CLL cells are perfectly targetable by CAP-100 which led to a complete inhibition of CCR7-mediated migration and induced strong target cell killing through antibody-dependent cell-mediated cytotoxicity, irrespective of previous or contemporary ibrutinib administration. Together, these results validate the therapeutic utility of CAP-100 as a next-line single-agent therapy for CLL patients who failed to ibrutinib and confirm that CAP-100 and ibrutinib have complementary non-overlapping mechanisms of action, potentially allowing for combination therapy.
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- 2021
9. Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL
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Javier Loscertales, Tamara Mateu-Albero, Cecilia Muñoz-Calleja, Fernando Terrón, Carlos Cuesta-Mateos, Raquel Juárez-Sánchez, and Wim Mol
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Receptors, CCR7 ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Immunology ,Antineoplastic Agents ,C-C chemokine receptor type 7 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Report ,antibody ,hemic and lymphatic diseases ,CAP-100 ,medicine ,Animals ,Humans ,Immunology and Allergy ,Antibodies, Blocking ,Lymph node ,030304 developmental biology ,0303 health sciences ,business.industry ,Antibodies, Monoclonal ,Cancer ,Immunotherapy ,lymph node ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chemotaxis, Leukocyte ,Macaca fascicularis ,Haematopoiesis ,medicine.anatomical_structure ,Tumor progression ,Immunoglobulin G ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy ,business ,CLL ,CCR7 ,Homing (hematopoietic) - Abstract
Lymph node (LN) is a key tissue in the pathophysiology of mature blood cancers, especially for chronic lymphocytic leukemia (CLL). Within the multiple de-regulated pathways affecting CLL homeostasis, the CC-chemokine receptor 7 (CCR7) grants homing of CLL cells into the LN where protective environments foster tumor progression. To cover the lack of specific therapies targeting the CCR7-dependence of CLL to enter into the LN, and aiming to displace the disease from LN, we generated CAP-100, an antibody that specifically binds to hCCR7 and neutralizes its ligand-binding site and signaling. In various in vitro and in vivo preclinical models CAP-100 strongly inhibited CCR7-induced migration, extravasation, homing, and survival in CLL samples. Moreover, it triggered potent tumor cell killing, mediated by host immune mechanisms, and was effective in xenograft models of high-risk disease. Additionally, CAP-100 showed a favorable toxicity profile on relevant hematopoietic subsets. Our results validated CAP-100 as a novel therapeutic tool to prevent the access of CLL cells, and other neoplasia with nodal-dependence, into the LN niches, thus hitting a central hub in the pathogenesis of cancer. The first-in-human clinical trial (NCT04704323), which will evaluate this novel therapeutic approach in CLL patients, is pending.
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- 2021
10. Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID‐19 patients
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Hugh T. Reyburn, Luciana del Campo Guerola, Santiago Sánchez-Alonso, Hortensia de la Fuente, Arantzazu Alfranca, Ligia Gabrie, Maria J. Calzada, José Miguel Rodríguez-Frade, Ana Marcos-Jimenez, Pedro Martínez-Fleta, Mar Valés-Gómez, Miguel Sampedro-Núñez, Enrique Martin-Gayo, Cecilia Muñoz-Calleja, Ildefonso Sánchez-Cerrillo, Tamara Mateu-Albero, Ana Alcaraz-Serna, José M. Casasnovas, Francisco Sánchez-Madrid, Margarita López-Trascasa, Celia López-Sanz, Santos Castañeda, Laura Esparcia, Isidoro González-Álvaro, UAM. Departamento de Medicina, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación 'la Caixa', European Commission, and Comunidad de Madrid
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0301 basic medicine ,Male ,Coronavirus disease 2019 (COVID-19) ,Medicina ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,Immunity to infection ,immunoglobulins ,macromolecular substances ,SARS‐CoV‐2 ,03 medical and health sciences ,Clinical ,0302 clinical medicine ,Immune system ,Immunity ,COVID‐19 ,Lymphopenia ,Follicular phase ,Immunology and Allergy ,Humans ,complement ,Lymphocyte Count ,Aged ,B-Lymphocytes ,Respiratory Distress Syndrome ,biology ,Research Article|Clinical ,SARS-CoV-2 ,COVID-19 ,Complement C5 ,Complement C4 ,Complement C3 ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,immunity ,Peripheral blood ,Immunoglobulin A ,Killer Cells, Natural ,030104 developmental biology ,Immunoglobulin M ,Immunoglobulin G ,Humoral immunity ,biology.protein ,Female ,Antibody ,030215 immunology ,Research Article - Abstract
SARS‐CoV‐2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID‐19. We investigated whether the specific immune responses in the peripheral blood of 276 patients associated to severity and progression of COVID‐19. At admission, dramatic lymphopenia of T, B and NK cells associated to severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56‐CD16+ NK‐cells increased. Regarding humoral immunity, levels of IgM, IgA and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID‐19 patients, associating severity with an imbalanced humoral response and identifying new targets for therapeutic intervention., The study was funded by grants SAF2017-82886-R to FS-M from the Ministerio de Economía y Competitividad, and from “La Caixa Banking Foundation” (HR17-00016) to FS-M. Grant PI018/01163 to CMC and grant PI19/00549 to AA were funded by Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Spain. SAF2017-82886-R, PI018/01163 and PI19/00549 grants were also cofunded by European Regional Development Fund, ERDF/FEDER. This work has been funded by grants Fondo Supera COVID (CRUE-Banco de Santander) to FSM, and “Ayuda Covid 2019” from Comunidad de Madrid.
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- 2020
11. Author response for 'Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID‐19 patients'
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Luciana del Campo Guerola, Maria J. Calzada, Santos Castañeda, José M. Casasnovas, Santiago Sánchez-Alonso, Ana Marcos-Jimenez, Celia López-Sanz, Ana Alcaraz-Serna, Miguel Sampedro-Núñez, Hugh T. Reyburn, Francisco Sánchez-Madrid, Margarita López-Trascasa, Cecilia Muñoz-Calleja, Ligia Gabrie, Arantzazu Alfranca, Ildefonso Sánchez-Cerrillo, Isidoro González-Álvaro, José Miguel Rodríguez-Frade, Tamara Mateu-Albero, Enrique Martin-Gayo, Mar Valés-Gómez, Hortensia de la Fuente, Laura Esparcia, and Pedro Martínez-Fleta
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Consumption (economics) ,Coronavirus disease 2019 (COVID-19) ,Immunology ,biology.protein ,Biology ,Antibody ,Complement (complexity) - Published
- 2020
12. IL-6 serum levels predict severity and response to Tocilizumab in COVID-19: an observational study
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José María Galván-Román, Sebastián C. Rodríguez-García, Emilia Roy-Vallejo, Ana Marcos-Jiménez, Santiago Sánchez-Alonso, Carlos Fernández-Díaz, Ana Alcaraz-Serna, Tamara Mateu-Albero, Pablo Rodríguez-Cortes, Ildefonso Sánchez-Cerrillo, Laura Esparcia, Pedro Martínez-Fleta, Celia López-Sanz, Ligia Gabrie, Luciana del Campo Guerola, Carmen Suárez-Fernández, Julio Ancochea, Alfonso Canabal, Patricia Albert, Diego A. Rodríguez-Serrano, Juan Mariano Aguilar, Carmen del Arco, Ignacio de los Santos, Lucio García-Fraile, Rafael de la Cámara, José María Serra, Esther Ramírez, Tamara Alonso, Pedro Landete, Joan B. Soriano, Enrique Martín-Gayo, Arturo Fraile Torres, Nelly Daniela Zurita Cruz, Rosario García-Vicuña, Laura Cardeñoso, Francisco Sánchez-Madrid, Arantzazu Alfranca, Cecilia Muñoz-Calleja, Isidoro González-Álvaro, Teresa Alvarado, Pablo Martínez, Francisco Javier de la Cuerda Llorente, Natalia Villalba, Mónica Negro, Elvira Contreras, Ana del Rey, Cristina Santiago, Manuel Junquera, Raquel Caminero, Francisco Javier Val, Sonia González, Marta Caño, Isabel López, Andrés von Wernitz, Bárbara Retana, Iñigo Guerra, Jorge Sorando, Lydia Chao, María José Cárdenas, Verónica Espiga, Pablo Chicharro, Pedro Rodríguez, Iñigo Hernando Alday, Miguel Sampedro, Jorge Prada, Eukene Rojo Aldama, Yolanda Real, María Caldas, Sergio Casabona, Aitor Lanas-Gimeno, Rafael de la Camara, Angela Figuera Alvárez, Beatriz Aguadol, Alberto Morell, Amparo Ibáñez Zurriaga, María Pérez Abanades, Silvia Ruiz García, Tomás Gallego Aranda, María Ruiz, Concepción Martínez Nieto, Javier Aspa, Elena Fernández, Ma José Calzada, Reyes Tejedor, Judit Iglesias, Fernando Suarez, Juan Antonio Sánchez, Beatriz Abad, Carmen Suarez, Emilia Roy, Jesus Sanz, Eduardo Sanchez, Fernando Moldenhauer, Pedro Casado, Jose Curbelo, Angela Gutierrez, Azucena Bautista, Nuria Ruiz Giménez, Angelica Fernandez, Pedro Parra, Berta Moyano, Ana Barrios, Diego Real de Asua, Beatriz Sanchez, Carmen Saez, Marianela Ciudad, Desiré Navas, Laura Cardeñoso Domingo, María del Carmen Cuevas Torresano, Diego Domingo García, Teresa Alarcón Cavero, Alicia García Blanco, Alexandra Martín Ramírez, María Auxiliadora Semiglia Chong, Ainhoa Gutiérrez Cobos, Arturo Manuel Fraile Torres, Carmen Sanchez-Gonzalez, Antonio Fernádez Perpén, Carolina Díaz Pérez, Joan Soriano, Carolina Cisneros, Elena García Castillo, Francisco Javier García Pérez, Rosa María Girón, Celeste Marcos, Enrique Zamora, Patricia García García, Santos Castañeda, Sebastián Rodríguez-García, Irene Llorente Cubas, Eva G. Tomero, Noelia García Castañeda, Ana Ma Ortiz, Cristina Valero, Miren Uriarte, and Nuria Montes
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0301 basic medicine ,ARDS ,CAR, chimeric antigen receptor ,medicine.medical_treatment ,Invasive Mechanical Ventilation ,chemistry.chemical_compound ,0302 clinical medicine ,SatO2, mean oxygen saturation ,Interquartile range ,Fraction of inspired oxygen ,Immunology and Allergy ,030212 general & internal medicine ,COVID-19, coronavirus disease 2019 ,PaO2/FiO2, arterial oxygen tension/fraction of inspired oxygen ratio ,TNF, tumor necrosis factor ,AUC, Area under curve ,AEMPS, Spanish Agency for Drugs and Health Devices ,Tocilizumab ,CRS, cytokine release syndrome ,PCT, procalcitonin ,Cytokine release syndrome ,CRP, C-reactive protein ,LR, negative likelihood ratio ,medicine.medical_specialty ,Immunology ,LR+, positive likelihood ratio ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,TCZ, Tocilizumab ,Survival rate ,ARDS, acute respiratory distress syndrome ,IQR, interquartile range ,Mechanical ventilation ,business.industry ,Interleukin-6 ,COVID-19 ,Odds ratio ,PaO2, arterial oxygen tension ,medicine.disease ,IL, interleukin ,ROC, receiver operating characteristic ,030104 developmental biology ,IMV, invasive mechanical ventilation ,chemistry ,COPD, chronic obstructive pulmonary disease ,STROBE, Strengthening the Reporting of Observational Studies in Epidemiology ,business ,SD, standard deviation - Abstract
Background COVID-19 patients can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome (ARDS) requiring invasive mechanical ventilation (IMV). Since interleukin-6 (IL-6) is a relevant cytokine in ARDS, the blockade of its receptor with Tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective To determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods Retrospective observational study performed in hospitalized patients diagnosed of COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with pre- and post-administration of TCZ. Multivariable logistic and linear regressions, and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio (PaO2/FiO2) or mortality. Results One hundred and forty-six patients were studied, predominantly male (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels>30 pg/ml was the best predictor for IMV (OR:7.1; p30 pg/ml predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration., Baseline IL-6 serum levels>30 pg/ml identify severe COVID-19 patients and should be used to guide the intervention with IL-6R inhibitors, aiming to improve their use in an uncertain and evolving therapeutic scenario.
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- 2020
13. Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19
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Laura Esparcia, Miguel Sampedro-Núñez, Enrique Martin-Gayo, Arantzazu Alfranca, Ildefonso Sánchez-Cerrillo, Luciana del Campo Guerola, Santos Castañeda, Ana Marcos-Jimenez, Ligia Gabrie, Pedro Martínez-Fleta, Ana Alcaraz-Serna, Santiago Sánchez-Alonso, Tamara Mateu-Albero, Celia López-Sanz, Margarita López-Trascasa, Francisco Sánchez-Madrid, Hortensia de la Fuente, Isidoro González-Álvaro, Maria J. Calzada, and Cecilia Muñoz-Calleja
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Antibody-dependent cell-mediated cytotoxicity ,medicine.diagnostic_test ,biology ,business.industry ,Flow cytometry ,Complement system ,Pathogenesis ,Immune system ,Peripheral blood lymphocyte ,Immunology ,Humoral immunity ,medicine ,biology.protein ,Antibody ,business - Abstract
BackgroundSARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the pathogenesis and outcome of COVID-19. We aimed to investigate which specific responses from either cellular or humoral immunity associate to severity and progression of COVID-19.MethodsA cohort of 276 patients classified in mild, moderate and severe, was studied. Peripheral blood lymphocyte subpopulations were quantified by flow cytometry, and immunoglobulins and complement proteins by nephelometry.ResultsAt admission, dramatic lymphopenia of T, B and NK cells associated to severity. However, only the proportion of B cells increased, while T and NK cells appeared unaffected. Accordingly, the number of plasma cells and circulating follicular helper T cells (cTfh) increased, but levels of IgM, IgA and IgG were unaffected. When degrees of severity were considered, IgG was lower in severe patients, suggesting an IgG consumption by complement activation or antibody-dependent cellular cytotoxicity (ADCC). Activated CD56-CD16+ NK-cells, which mediate ADCC, were increased. Regarding complement, C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, compared to healthy donors. Moreover, IgG and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier.ConclusionOur study provides important clues to understand the immune response observed in COVID-19 patients, which is probably related to viral clearance, but also underlies its pathogenesis and severity. This study associates for the first time COVID-19 severity with an imbalanced humoral immune response characterized by excessive consumption of IgG and C4, identifying new targets for therapeutic intervention.
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- 2020
14. Differential Redistribution of Activated Monocyte and Dendritic Cell Subsets to the Lung Associates with Severity of COVID-19
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Julio Ancochea, Cecilia Muñoz-Calleja, Arantzazu Alfranca, Pedro Landete, Laura Esparcia, Ana Sanchez-Azofra, Ana Alcaraz-Serna, Isidoro González-Álvaro, Joan B. Soriano, Tamara Mateu-Albero, Ana Marcos-Jimenez, Pedro Martínez-Fleta, Ildefonso Sánchez-Cerrillo, Enrique Martin-Gayo, Ignacio Santos, Santiago Sánchez-Alonso, Celia López-Sanz, Ligia Gabrie, Maria J. Calzada, Luciana del Campo Guerola, Elena Ávalos, Francisco Sánchez-Madrid, and Beatriz Aldave
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ARDS ,Lung ,business.industry ,Monocyte ,T cell ,Inflammation ,Dendritic cell ,medicine.disease ,Article ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,medicine.symptom ,business ,CD8 - Abstract
The SARS-CoV-2 is responsible for the pandemic COVID-19 in infected individuals, who can either exhibit mild symptoms or progress towards a life-threatening acute respiratory distress syndrome (ARDS). It is known that exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8+ T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. With the aim to improve the knowledge in this area, we developed a cross-sectional study, in which we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood of COVID-19 patients with different clinical severity in comparison with healthy control individuals. Furthermore, these subpopulations and their association with antiviral effector CD8+ T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Collectively, our results suggest that inflammatory transitional and non-classical monocytes preferentially migrate from blood to lungs in patients with severe COVID-19. CD1c+ conventional dendritic cells also followed this pattern, whereas CD141+ conventional and CD123hi plasmacytoid dendritic cells were depleted from blood but were absent in the lungs. Thus, this study increases the knowledge on the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies to fight SARS-CoV-2 infection.Single-sentence summaryDepletion from the blood and differential activation patterns of inflammatory monocytes and CD1c+ conventional dendritic cells associate with development of ARDS in COVID-19 patients.
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- 2020
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15. A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
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Cristina López-Rodríguez, Shu Zhen Chong, Jaime García-Prieto, Carlos Silvestre-Roig, Monica Gomez-Parrizas, José M. Adrover, Juan A. Quintana, Jorge López, Francisco Abad-Santos, Ana Victoria Lechuga-Vieco, David Sancho, Maximilien Evrard, Christian Weber, María A. Moro, Linnea A. Weiss, Maria Casanova-Acebes, Lai Guan Ng, Alexander Zarbock, Itziar Cossío, Borja Ibanez, Carlos del Fresno, Françoise Bachelerie, Jan Rossaint, Hector Huerga-Encabo, Alejandra Aroca-Crevillen, Andrés Hidalgo, Sandra Martín-Salamanca, Cecilia Muñoz-Calleja, Georgiana Crainiciuc, Kiril Bidzhekov, Karl Balabanian, Oliver Soehnlein, María Isabel Cuartero, Iván Ballesteros, RS: Carim - B01 Blood proteins & engineering, Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Ministerio de Economía, Industria y Competitividad (España), European Commission, European Research Council, Deutsche Forschungsgemeinschaft, German Centre for Cardiovascular Research, European Regional Development Fund (ERDF/FEDER), Fundación ProCNIC, Instituto de Salud Carlos III - ISCIII, Centro de Investigación Biomedica en Red - CIBER, Unión Europea. Comisión Europea, Deutsche Forschungsgemeinschaft (Alemania), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), and German Research Foundation
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0301 basic medicine ,Male ,Chemokine ,Time Factors ,Neutrophils ,Chemokine CXCL2 ,CXCR4 ,Chemokine receptor ,0302 clinical medicine ,Neutrophil aging ,Candida albicans ,circadian clock ,Immunology and Allergy ,CXC chemokine receptors ,Cells, Cultured ,Cellular Senescence ,Mice, Knockout ,0303 health sciences ,Neutrophil ,Compartmentalization (psychology) ,Bmal ,Cell biology ,Circadian Rhythm ,3. Good health ,neutrophil aging ,CXCL2 ,myocardial infarction ,Infectious Diseases ,Neutrophil Infiltration ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,medicine.symptom ,Infection ,EXPRESSION ,Receptors, CXCR4 ,BONE-MARROW ,Immunology ,LEUKOCYTE ADHESION ,Inflammation ,Biology ,Circadian clock ,1CXCR2 ,03 medical and health sciences ,Phagocytosis ,INFLAMMATION ,Immunity ,FLUORESCENT PROTEIN ,medicine ,OSCILLATIONS ,Animals ,Humans ,MODULATION ,030304 developmental biology ,RELEASE ,CXCR2 ,infection ,Mice, Inbred C57BL ,Myocardial infarction ,Bmal1 ,030104 developmental biology ,inflammation ,biology.protein ,SELECTIN ,Blood Vessels ,030217 neurology & neurosurgery - Abstract
Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection. Neutrophils display circadian oscillations in numbers and phenotype in the circulation. Adrover and colleagues now identify the molecular regulators of neutrophil aging and show that genetic disruption of this process has major consequences in immune cell trafficking, anti-microbial defense, and vascular health., This study was supported by Intramural grants from A∗STAR to L.G.N., BES-2013-065550 to J.M.A., BES-2010-032828 to M.C.-A, and JCI-2012-14147 to L.A.W (all from Ministerio de Economía, Industria y Competitividad; MEIC). Additional MEIC grants were SAF2014-61993-EXP to C.L.-R.; SAF2015-68632-R to M.A.M. and SAF-2013-42920R and SAF2016-79040Rto D.S. D.S. also received 635122-PROCROP H2020 from the European Commission and ERC CoG 725091 from the European Research Council (ERC). ERC AdG 692511 PROVASC from the ERC and SFB1123-A1 from the Deutsche Forschungsgemeinschaft were given to C.W.; MHA VD1.2/81Z1600212 from the German Center for Cardiovascular Research (DZHK) was given to C.W. and O.S.; SFB1123-A6 was given to O.S.; SFB914-B08 was given to O.S. and C.W.; and INST 211/604-2, ZA 428/12-1, and ZA 428/13-1 were given to A.Z. This study was also supported by PI12/00494 from Fondo de Investigaciones Sanitarias (FIS) to C.M.; PI13/01979, Cardiovascular Network grant RD 12/0042/0054, and CIBERCV to B.I.; SAF2015-65607-R, SAF2013-49662-EXP, and PCIN-2014-103 from MEIC; and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) to A.H. The CNIC is supported by the MEIC and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).
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- 2019
16. Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease
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María L. Toribio, Patricia Fuentes, Tamara Mateu-Albero, Valle Gómez García de Soria, Laura Cardeñoso, Yaiza Pérez-García, Lorena Vega-Piris, Cecilia Muñoz-Calleja, Blanca Andrea Sánchez-López, Marina García-Peydró, Juan Alcaín, Itxaso Portero-Sainz, Raquel Juárez-Sánchez, Ana Marcos-Jiménez, Carlos Cuesta-Mateos, and Paula Díaz-Fernández
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Receptors, CCR7 ,medicine.drug_class ,medicine.medical_treatment ,T-Lymphocytes ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 7 ,Graft vs Leukemia Effect ,Hematopoietic stem cell transplantation ,Monoclonal antibody ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,immune system diseases ,In vivo ,Immunity ,medicine ,Humans ,Transplantation ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,virus diseases ,hemic and immune systems ,Hematology ,Lymphatic system ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Antibody ,business ,030215 immunology - Abstract
Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7)+ T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7+ cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7+ T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naive and central memory T cells toward CCR7 ligands and depleted target CCR7+ subsets through complement activation. Both mechanisms of action spared CCR7− subsets, including effector memory and effector memory CD45RA+ T cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7+ T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed.
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- 2019
17. Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis
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Guadalupe Herrera, Elisenda Alari-Pahissa, Alexandru Vlagea, David San Segundo, Juana Gil-Herrera, María Gema Salgado, J. M. Ferrer, Silvia Presas-Rodríguez, Cecilia Muñoz-Calleja, Juan Pablo Cuello, Patricia Urbaneja, Carmen Cámara, Herena Eixarch, Luisa M. Villar, Breogán Rodríguez-Acevedo, Rocío Hernández-Clares, Luis Querol, Eugenia Martinez-Hernandez, Virginia Meca-Lallana, Francisco Gascón-Gimenez, Tamara Castillo-Triviño, María Jesús Pinto-Medel, Jose E Martínez-Rodríguez, Margarita Massot, Agustín Oterino, Aina Teniente-Serra, Alfonso Muriel, Ernesto Roldán, Larraitz Aragón, Montserrat Gómez-Gutiérrez, Esther Moga, Eulalia Rodríguez-Martín, Noelia Villarrubia, and Alvaro Prada
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Intraclass correlation ,Concordance ,T cell ,Clinical Biochemistry ,Immunology ,Biochemistry ,Spearman's rank correlation coefficient ,Multiple sclerosis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Multicenter Studies as Topic ,Flow cytometry ,B cell ,business.industry ,Biochemistry (medical) ,General Medicine ,Interferon-beta ,Middle Aged ,medicine.disease ,Flow Cytometry ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,CD5 ,business ,CD8 ,Biomarkers - Abstract
Background and objectives: Percentages of blood CD19 + CD5 + B cells and CD8 + perforin + T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19 + CD5 + B cell and 0.89 (CI: 0.85-0.93) for CD8 + perforin + T cell quantification; Spearman r was 0.92 (0.89-0.95; p < 0.0001) and 0.92 (0.88-0.95; p < 0.0001) respectively. All centres obtained z-scores 5 0.5 for both biomarkers. Conclusion: Homogenous percentages of CD19 + CD5 + B cells and CD8 perforin + T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.
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- 2018
18. Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets
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Carlos Cuesta-Mateos, Ana Alcaraz-Serna, Beatriz Somovilla-Crespo, and Cecilia Muñoz-Calleja
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lcsh:Immunologic diseases. Allergy ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Review ,Monoclonal antibody ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,hematological malignancies ,non-lineage antigens ,Tumor microenvironment ,biology ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,monoclonal antibody ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Rituximab ,immunotherapy ,Antibody ,business ,lcsh:RC581-607 ,030215 immunology ,medicine.drug ,mechanism of action - Abstract
Today, monoclonal antibodies (mAbs) are a widespread and necessary tool for biomedical science. In the hematological cancer field, since rituximab became the first mAb approved by the FDA for the treatment of B-cell malignancies, a number of effective mAbs targeting lineage-specific antigens (LSA) have been successfully developed. Non-lineage related antigens (NLSAs) are molecules which are not restricted to specific leukocyte subsets or tissues, but play relevant pathogenic roles in blood cancers including the development, proliferation, survival and refractoriness to therapy of tumor cells. In consequence, efforts to target NLSAs have resulted in a plethora of mAbs -marketed or in development- to achieve different goals like neutralizing oncogenic pathways, blocking tumor-related chemotactic pathways, mobilizing malignant cells from tumor microenvironment (TME) to peripheral blood, modulating immune-checkpoints, or delivering cytotoxic drugs into tumor cells. Here, we extensively review several novel mAbs directed against NLSAs undergoing clinical evaluation for treating hematological malignancies. The review focuses on the structure of these antibodies, proposed mechanisms of action (MOA), efficacy and safety profile in clinical studies, and their potential applications in the treatment of hematological malignancies.
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- 2018
19. P-Selectin preserves immune tolerance in mice and is reduced in human cutaneous lupus
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Cecilia Muñoz-Calleja, Rafael González-Tajuelo, María de la Fuente-Fernández, Santos Castañeda, Angeles Juarranz, Alicia Pérez-Frías, Reyes Tejedor, Carlos Gamallo, Javier Silván, Esther F Vicente-Rabaneda, Ana Urzainqui, and Marina Espartero-Santos
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0301 basic medicine ,Male ,Naive T cell ,T cell ,T-Lymphocytes ,Population ,Article ,Immune tolerance ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Immune Tolerance ,Lupus Erythematosus, Cutaneous ,Medicine ,Animals ,Humans ,education ,Autoantibodies ,Skin ,education.field_of_study ,Multidisciplinary ,Lupus erythematosus ,Systemic lupus erythematosus ,business.industry ,Interleukin-17 ,Germinal center ,medicine.disease ,Germinal Center ,Lymphocyte Subsets ,Interleukin-10 ,Mice, Inbred C57BL ,P-Selectin ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Female ,business ,Spleen ,030215 immunology - Abstract
Mice deficient in P-Selectin presented altered immunity/tolerance balance. We have observed that the absence of P-Selectin promotes splenomegaly with reduced naïve T cell population, elevated activated/effector T cell subset, increased germinal center B and Tfh populations and high production of autoreactive antibodies. Moreover, 1.5-3-month-old P-selectin KO mice showed reduced IL-10-producing leukocytes in blood and a slightly reduced Treg population in the skin. With aging and, coinciding with disease severity, there is an increase in the IL17+ circulating and dermal T cell subpopulations and reduction of dermal Treg. As a consequence, P-Selectin deficient mice developed a progressive autoimmune syndrome showing skin alterations characteristic of lupus prone mice and elevated circulating autoantibodies, including anti-dsDNA. Similar to human SLE, disease pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli, and a complex pattern of autoantibodies. More important, skin biopsies of cutaneous lupus erythematosus patients did not show increased expression of P-Selectin, as described for other inflammatory diseases, and the number of vessels expressing P-Selectin was reduced.
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- 2017
20. Taller de Autoinmunidad 2013 de la Sociedad Española de Inmunología. Anticuerpos anticitoplasma de neutrófilo (ANCA)
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Marco Antonio Montes Cano, Margarita Rodríguez Mahou, Lourdes Mozo Avellaned, Juan Francisco Rodríguez Gutiérrez, José Marcos García Pacheco, Garbiñe Roy Ariño, Margarita García Marcos, Jesús Ontañón Rodríguez, Dora Pascual Salcedo Pascual, J. Jimenez, Juana Rodríguez Delgado, Inmaculada Alarcón Torres, Francisco Pujalte Mora, Estela Paz Artal, María Aránzazu Pacho De Lucas, Luis Fernández Pereira, Ángela Carrasco Sayalero, María José Amengual Guedan, Alexandru Vlagea, Francisco Javier Muñoz Vico, M. Rosa Julià Benique, Pedro Martínez García, José Javier Cid Fernández, Pablo Eiras Martínez, Esther Ocaña Pérez, Eduardo Villegas Martín, Silvina Torio Gómez, Antonio Serrano, Montserrat Alsina Donadeu, Álvaro Prada Iñurrategui, Carmen Rodríguez Hernández, Marcos López Hoyos, Rita Álvarez Doforno, Manuel Espárrago Rodilla, Yvelise Barrios del Pino, Cecilia Muñoz Calleja, Aurora Jurado Roger, Olga Montes Ares, M. Luisa Vargas Pérez, Paz Laporta Martín, Aresio Plaza López, Carmen Gelpí Sabater, Mila Garcia, Romina Dieli Crimi, Sara Calleja Antolín, Eva María Cabeza Martínez Cáceres, Ana Marín Sánchez, Goitzane Marcaida Benito, Raquel Sáez, Rosa María Pastor Barellas, M. Inmaculada Alcalá Peña, Laura Jaimez Gámiz, María Belén Aparicio Hernández, Alberto Torio Ruiz, Odette Vinyas Gomis, Jordi Bas, Carmen Jiménez Garófano, Alfonso Sánchez Ibarrola, Delia Almeida González, Concepción González Rodríguez, and María José Martínez Becerra
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business.industry ,Immunology ,Medicine ,business - Published
- 2013
21. Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication
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A Arteche-López, Beatriz Aguado, Luisa M. Villar, Cecilia Muñoz-Calleja, M. González-Pardo, R de la Cámara, Anna Kreutzman, A Alegre, Mercedes Espiño, P Sanz Martín, and D García Belmonte
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Adult ,CD4-Positive T-Lymphocytes ,Male ,medicine.medical_treatment ,CD4-CD8 Ratio ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Autologous stem-cell transplantation ,medicine ,Humans ,Progenitor cell ,Autografts ,Multiple myeloma ,Aged ,Transplantation ,B-Lymphocytes ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Immunology ,Female ,Stem cell ,business ,Multiple Myeloma ,030215 immunology ,Follow-Up Studies - Abstract
The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naive, effector, central memory and regulatory), B-cells (naive, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naive cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.
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- 2016
22. A high migratory capacity of donor T-cells in response to the lymph node homing receptor CCR7 increases the incidence and severity of GvHD
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Beatriz Colom-Fernández, V López-Huete, Cecilia Muñoz-Calleja, Ana Marcos-Jiménez, Itxaso Portero-Sainz, Carlos Cuesta-Mateos, C Fernández-Arandojo, Beatriz Somovilla-Crespo, Anna Kreutzman, A de Rosendo-Serrano, V Gómez-García de Soria, Mercedes Royg, A Ramírez-Mengíbar, and Lorena Vega-Piris
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Receptors, CCR7 ,Adolescent ,CD4-CD8 Ratio ,Receptors, Lymphocyte Homing ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 7 ,Severity of Illness Index ,Pathogenesis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,immune system diseases ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,L-Selectin ,Lymphocyte homing receptor ,Aged ,Transplantation ,Chemokine CCL21 ,business.industry ,Chemotaxis ,Incidence ,CCL19 ,virus diseases ,hemic and immune systems ,Hematology ,Middle Aged ,medicine.disease ,Tissue Donors ,surgical procedures, operative ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Immunology ,Chemokine CCL19 ,Female ,business ,CD8 ,030215 immunology ,Homing (hematopoietic) - Abstract
The pathogenesis of GvHD involves migration of donor T-cells into the secondary lymphoid organs in the recipient, which is steered by two homing molecules, CD62L and CCR7. Therefore, we investigated whether the migratory capacity of donor T-cells is associated with GvHD. This single center prospective study included 85 donor-recipient pairs. In vitro chemotaxis assays of the lymphocytes of the apheresis product were performed in parallel to the analysis of CD62L and CCR7 by flow cytometry. The migratory index to the CCR7 ligands, CCL19 and CCL21, was higher in T-cells from donors whose recipients will develop GvHD. Similarly, the acute GvHD (aGvHD) group received higher percentage of CD4+CCR7+ T-cells, whereas chronic GvHD (cGvHD) patients were transplanted with higher percentages of CD8+CCR7+ T-cells compared with the non-GvHD group. These results were confirmed when patients were subdivided according to degrees of severity. Further, multivariate analysis confirmed that the proportions of CCR7+ CD4+ and CCR7+ CD8+ T-cells are risk factors for the development and severity of aGvHD and cGvHD, respectively. Functional experiments demonstrated that CCR7+ T-cells exhibited higher potential for activation than CCR7- T-cells did. We therefore propose that the selective depletion of CCR7-expressing T-cells may be an effective preventive therapy for GvHD.
- Published
- 2016
23. Indole-3-carbinol synergizes with and restores fludarabine sensitivity in chronic lymphocytic leukemia cells irrespective of p53 activity and treatment resistances
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Carolina Martínez-Laperche, Nerea Rebolleda, Juan M. Zapata, Ismael Buño, Beatriz Somovilla-Crespo, Gema Perez-Chacon, Cecilia Muñoz-Calleja, European Commission, Ministerio de Economía y Competitividad (España), Fundación LAIR, Consejo Superior de Investigaciones Científicas (España), and Asociación Española Contra el Cáncer
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0301 basic medicine ,Cancer Research ,Stromal cell ,Indoles ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Cytotoxic T cell ,Animals ,Humans ,business.industry ,Drug Synergism ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Caspase 9 ,Fludarabine ,Leukemia ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunology ,Toxicity ,Mutation ,Cancer research ,Tumor Suppressor Protein p53 ,business ,IGHV@ ,Immunoglobulin Heavy Chains ,Adjuvant ,Vidarabine ,medicine.drug - Abstract
[Purpose]: Chronic lymphocytic leukemia (CLL) still is lacking a cure. Relapse and development of refractoriness to current treatments are common. New therapies are needed to improve patient prognosis and survival. [Experimental design]: Indole-3-carbinol (I3C) is a natural product with antitumor properties already clinically tested. The effect of I3C, F-ara-A, and combinations of both drugs on CLL cells from patients representing different Rai stages, IGHV mutation status, cytogenetic alterations, p53 functionality, and treatment resistances was tested, as well as the toxicity of these treatments in mice. [Results]: I3C induces cytotoxicity in CLL cells but not in normal lymphocytes. I3C strongly synergized with F-ara-A in all CLL cells tested, including those with p53 deficiency and/or F-ara-A resistance. The mechanism of cell death involved p53-dependent and -independent apoptosis. The combination of I3C + F-ara-A was equally effective in CLL cells irrespective of IGHV mutation stage and patient refractoriness. Moreover, CLL survival and treatment resistance induced by co-culturing CLL cells on stroma cells were overcome by the combinatory I3C + F-ara-A treatment. No toxicity was associated with the combined I3C + fludarabine treatment in mice. [Conclusions]: I3C in combination with F-ara-A is highly cytotoxic in CLL cells from refractory patients and those with p53 deficiency. The striking dose reduction index for F-ara-A in combination with I3C would reduce fludarabine toxicity while having a similar or better anti-CLL effectiveness. Moreover, the low toxicity of I3C, already clinically tested, supports its use as adjuvant and combinatory therapy in CLL, particularly for patients with relapsed or refractory disease., This work was supported by grants from the Ministerio de Economia y Competitividad (PI12/01135 to J.M. Zapata, PI12/00494 to C. Muñoz-Calleja, and PI11/00708 to I. Buño) and from the Asociacion Española Contra el Cancer and Fundacion LAIR (to I. Buño). G. Perez-Chacon was the recipient of a JAE Doc contract from CSIC. The cost of this publication was paid in part by FEDER funds.
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- 2016
24. Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia
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Javier Loscertales, Fernando Terrón, Anna Kreutzman, Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Itxaso Portero-Sainz, Juan José Pérez-Villar, and Beatriz Colom-Fernández
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Cancer Research ,Receptors, CCR7 ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Antibodies, Monoclonal, Humanized ,Immunophenotyping ,Antibodies, Monoclonal, Murine-Derived ,immune system diseases ,Chemoimmunotherapy ,Risk Factors ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Humans ,Alemtuzumab ,business.industry ,Immunotherapy ,medicine.disease ,Genes, p53 ,Leukemia, Lymphocytic, Chronic, B-Cell ,Fludarabine ,Leukemia ,Oncology ,Monoclonal ,business ,medicine.drug - Abstract
Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti-CCR7 mAb is an effective and promising future treatment in high-risk CLL.
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- 2014
25. Autoantibodies against TIF-1-γ and CADM-140 in Spanish patients with clinically amyopathic dermatomyositis (CADM): clinical significance and diagnostic utility
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Itxaso Portero-Sainz, R. Tejedor, Beatriz Colom-Fernández, C. Cuesta-Mateos, Cecilia Muñoz-Calleja, M.A. Martínez, C. García-García, C. Juarez, M.J. Concha-Garzón, and M.E. de las Heras-Alonso
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Dermatology ,Dermatomyositis ,Subacute cutaneous lupus erythematosus ,medicine ,Humans ,Clinical significance ,Myositis ,Aged ,Autoantibodies ,business.industry ,Interstitial lung disease ,Autoantibody ,Cancer ,Nuclear Proteins ,Middle Aged ,medicine.disease ,Infectious Diseases ,Spain ,Immunology ,Intercellular Signaling Peptides and Proteins ,Female ,Differential diagnosis ,business ,Apoptosis Regulatory Proteins ,Peptides ,Anti-SSA/Ro autoantibodies - Abstract
Background Patients with clinically amyopathic dermatomyositis (CADM) appear to be at risk for developing cancer and interstitial lung diseases, but population data to confirm this hypothesis are limited. Moreover, CADM presents cutaneous and histological findings that may overlap with subacute cutaneous lupus erythematosus (SCLE). Objectives To determine the association between myositis-specific autoantibodies, myositis-associated autoantibodies and CADM in Spanish patients. In addition, to study the usefulness of these autoantibodies in the differential diagnosis between CADM and SCLE. Methods Serum samples were tested for myositis-specific autoantibodies and myositis-associated autoantibodies through immunoprecipitation and other standardized methods. Results Anti-CADM-p140 and anti-p155 antibodies were the only myositis-specific autoantibodies found and were associated with interstitial lung diseases and cancer respectively. No myositis-associated autoantibodies were found in CADM. Moreover, clinical subsets and proportions seemed to differ from Asian cohorts, where anti-CADM-p140 is considered a CADM hallmark antibody and a risk factor for the development of interstitial lung disease. Interestingly, anti-SSA was highly associated with SCLE, whereas no myositis-specific autoantibodies were found in this entity. Limitations of the study Association between CADM and myositis-specific autoantibodies and differences between CADM and SCLE were tested on a relatively small cohort of patients. Conclusion There is an association between cancer-associated myositis and interstitial lung diseases and their hallmark autoantibodies in our cohort. In addition, the combined determination of myositis-specific autoantibodies and SSA autoantibodies may help to accurately discriminate SCLE from CADM.
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- 2013
26. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma
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Elena Fernández-Ruiz, Cristina Carballo-De Dios, Gema Perez-Chacon, Carlos Gamallo-Amat, Beatriz Somovilla-Crespo, Fernando Terrón, Juan M. Zapata, Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Juan José Pérez-Villar, Manuel Alfonso-Pérez, Amada E Beltrán, Fundación Leucemia y Linfoma, Fundación Vistare, Institute for Molecular Medicine (US), Instituto de Salud Carlos III, and UAM. Departamento de Medicina
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Receptors, CCR7 ,Cancer Research ,Lymphoma ,medicine.drug_class ,Medicina ,Chronic lymphocytic leukemia ,C-C chemokine receptor type 7 ,Apoptosis ,Lymphoma, Mantle-Cell ,Mice, SCID ,Biology ,Monoclonal antibody ,Chemokine receptor ,Mice ,In vivo ,Mice, Inbred NOD ,immune system diseases ,medicine ,Animals ,Humans ,Molecular Biology ,Animal ,Research ,Hematology ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Oncology ,Immunology ,Cancer research ,Inbred NOD ,Mantle cell lymphoma ,Female ,CCR7 - Abstract
[Background]: The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. [Methods]: NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. [Results]: The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. [Conclusions]: The anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies., BSC is supported by the Fundación Leucemia Linfoma and Fundación Vistare. Grants from the Fondo de Investigaciones Sanitarias to CMC (PI09/01336 and PI12/00494), JMZ (PI12/01135) and EFR (PI11/00128) and from IMMED to CMC supported this work.
- Published
- 2013
27. Efficacy and Safety of Dasatinib in Late Suboptimal Response CML Patients a Its Relation with Lymphocytosis, Lymphocyte Migration and Chemokine Receptor Expression
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Anna Kreutzman, Cesar Soto, Joaquin Martinez Lopez, Blanca Xicoy, Cecilia Muñoz-Calleja, Valentín García-Gutiérrez, Fermín Sánchez-Guijo, Raquel de Paz, Juan Luis Steegmann, Luis Felipe Casado, Beatriz Colom-Fernández, Isabel Montero, Rosa Ayala, and Concepción Boqué
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medicine.medical_specialty ,Lymphocytosis ,business.industry ,Pleural effusion ,Anemia ,Immunology ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dasatinib ,Clinical trial ,Basal (phylogenetics) ,Median follow-up ,Internal medicine ,medicine ,medicine.symptom ,business ,medicine.drug - Abstract
INTRODUCTION: In patients with so called "late suboptimal responses" (patient with complete cytogenetic response (CCyR) without major molecular response (MMR) after 18 months of imatinib) , the role of dasatinib has not been evaluated. Dasatinib has unique immunomodulatory effects especially on the proliferation and activation of T- and NK-cells. Yet, how dasatinib affects the migration of lymphocytes is unknown. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late suboptimal response (now considered as ELN2013 as warning). Another aim is to correlate new immunological aspects related to dasatinib and its possible correlation with responses. METHODS: We are presenting results of first 18 patients enrolled in the phase II DASAPOST study (NCT01802450). Main inclusion criteria were patients treated with late suboptimal response by ELN09 (CCyR without MMR after 18 months of treatment. Sokal risk groups were (L/I/H) 22.5%, 50% and 22.5%. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. An exhaustive lymphocyte migration study was done, including immunophenotipying pre and post samples (CD 45, CD3,CD8, CD16, CXCR3, CXCR4, CD56 and CCR7), migration assay (chemokines CXCL10, CCL19+CCL21 and CXCL12) and CXCL10 plasma concentration measured by ELISA. RESULTS: - Clinical: Median follow up was 288 days (100-380). Three out of 18 (16%) patients had discontinued dasatinib due to side effects (pancreatitis, pleural effusion and low grade, persistant side effects (fever, arthralgias, anemia and astenia). All patients have been evaluated at 3 months, 17 at 6 months and 11 at 12 months. Cumulative incidences by ITT of MMR by 3 and 6 months were 50% and 81%. Cumulative incidences by ITT of MR4.5 by 3 and 6 months were 18% and 25%, respectively. - Inmunological: Dasatinib intake induced a significant increase of NK-cells and decrease of percentage of T-cells. Further, it increased CD8+ T cells, while reducing the proportion of CD4+ T-cells among the total T-cells. With the first dose of dasatinib (to),the percentage of CCR7 was lower in CD4+ and CD8+ T-cells in the post-samples. Lymphocyte migration was studied with transwell assays. At t0, post-samples showed a reduced migratory capacity towards the chemokines CCL19 and CCL21 in both CD4+ and CD8+ T-cell subsets. Patients were classified as mobilizers (n=14) or non-mobilizers (n=3) depending on whether they experienced an increase in the absolute lymphocyte counts after the first intake of dasatinib or not, showing different lymphocyte distribution and migratory capacity. In order to study the long term effects of dasatinib, we calculated the fold change (FC) of absolute lymphocyte counts pre- and post-dasatinib intake. Patients were divided into two groups based on whether in the 3 months samples (t3) had a higher ("increase group") or a lower ("decrease group") FC compared with t0. The migratory capacity of these two groups was studied in basal conditions and towards CCL19+CCL21 or CXCL10. We found no differences in basal migration in the "increase "group, while, the basal migration in the "decrease" group was quite promoted at t0 and t3. Further, migration towards CCL19+21 in post-samples is even more inhibited in "increase" patients at t3, whereas in the "decrease" patients the inhibition is diminished. The patients were divided into two groups based on the achievement of MMR at t3. At t0 both patient groups had similar migratory capacity, however, at t3, responders maintained significantly impaired migratory capacity to CCL19+21, compared with non-responders. CONCLUSIONS: Our study shows, for the first time to our knowledge, that in patients treated with Imatinib and with late warning responses, switch to Dasatinib induced MMR in 83% of the patients, although 16% discontinued treatment because of toxicity. We reported for the first time that dasatinib has significant effects on lymphocyte migration, and these are associated with early response. Disclosures García-Gutierrez: Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Casado:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Sánchez-Guijo:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Boque:Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria. Muñoz-Calleja:BMS: Research Funding. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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- 2015
28. The Role of CMV Serostatus of the Donor in the Graft Lymphoid Composition and Prediction of Gvhd and CMV Reactivation
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Valle Gómez García de Soria, Cecilia Muñoz Calleja, Rafael de la Cámara, Ana Ramirez, Itxaso Portero Sainz, Ana Marcos, Anna Kreutzman, Carlos Fernández, Beatriz Colom Fernandez, Laura Cardeñoso, and Royg Mercedes
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CD3 ,Immunology ,C-C chemokine receptor type 7 ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biology ,medicine.disease ,Biochemistry ,Pathogenesis ,Transplantation ,surgical procedures, operative ,Graft-versus-host disease ,immune system diseases ,medicine ,biology.protein ,L-selectin ,CD8 - Abstract
Background. Cytomegalovirus (CMV) is a widespread persistent β–herpesvirus, which can cause severe complications during primary infection or reactivation in immunocompromised patients, such as after allogeneic stem cell transplantation (alloSCT). Another major complication associated with alloSCT is graft-versus-host disease (GVHD). The pathogenesis of GVHD involves migration of the transplanted donor naïve T-cells into the secondary lymphoid organs in the recipient, which is mainly steered by CD62L and CCR7. As these homing molecules have been associated with both acute GVHD (aGVHD) and chronic GVHD (cGVHD), we studied whether the CMV serostatus of the donor affects the lymphoid composition of the graft product and whether this phenotype can predict CMV reactivation and GVHD. Methods. This single-center study included 77 donor-recipient pairs who underwent alloSCT. 64 pairs were HLA identical, 12 had 1 mismatch and 3 had 2 mismatch. 36 donors were related to their recipients. All recipients were followed at least for 100 (aGVHD) or 360 days (cGVHD) after transplantation. 43 donors were CMV-seropositive (CMVpos) and 34 were CMV-seronegative (CMVneg). 62 recipients were CMVpos, and 32 of them developed CMV reactivation, 25 aGVHD and 30 cGVHD. Samples from the graft product (donor) were phenotyped by flow cytometry (CD45, CD3, CD8, CD4, CD62L, CCR7) and both frequency (freq) and absolute number (abs) of each T-cell subpopulation were analyzed. Results. When the donors were divided based on their CMV serostatus, we observed that the grafts from CMVpos donors had a lower freq of naïve (CCR7+CD62L+) CD4+ T-cells (of lymphocytes p=0.06, of CD3 p=0.06, of CD4 p=0.07) and naïve CD8+ T-cells (of leukocytes p=0.03, of lymphocytes p=0.041, of CD3 p=0.011, of CD8 p=0.012) compared to CMVneg donors. Further, the abs of transplanted naïve CD8+ T-cells was significantly lower in the grafts from CMVpos donors (p=0.048). No differences were observed in T-cells (CD3+, CD4+, CD8+). We next studied if the CMV-serostatus and T-cell phenotype of the graft associates with GVHD. CMVpos donors whose recipients developed aGVHD had higher abs (p=0.05) and freq of naïve CD8+ T-cells (of lymphocytes p=0.08, of CD3 p=0.08, of CD8 p=0.11) compared to those without aGVHD. The same trend was observed with abs (p=0.11) and freq of CCR7+CD4+ T-cells (of leukocytes p=0.15). Similarly, those CMVpos donors whose recipients developed cGVHD had higher abs (p=0.05) and freq of CCR7+CD8+ T-cells (of leukocytes p=0.03, of lymphocytes p=0.06). Further, cGVHD patients who received the transplant from CMVpos donors were infused with a higher freq of CD3+ (of leukocytes p=0.03) and CD4+ T cells (of leukocytes p=0.04) than patients who received a graft from CMVpos donors but did not develop cGVHD. In contrast, CMVneg donors who developed aGVHD had a higher freq of CD3+ (p=0.018) and CD4+ T-cells (p=0.09), whereas no differences were seen in the T-cell subpopulations. Conversely, the abs (p=0.08) and freq of CCR7+CD4+ T-cells (of leukocytes p=0.11) were higher in those who later developed cGVHD. To study whether the graft lymphoid composition can be used to predict CMV reactivation, we analyzed the lymphoid composition in the graft product of those donors (both CMVpos and CMVneg) whose recipients were CMV seropositive but did not develop any form of GVHD (to avoid the influence of GVHD in the reactivation of CMV). Despite the low number of patients (CMV reactivation n=9, and no CMV reactivation n=13), we observed trends of higher portion of CD4+ T-cells (p=0.09 of lymphocytes, of CD3 p=0.20) and CCR7+CD4+ T-cells (of lymphocytes p=0.18, of CD4 p=0.16) in those grafts that were transplanted into CMV seropositive recipients who did not reactivate CMV. Conclusions. CMVpos donors whose recipient developed either aGVHD or cGVHD had a higher abs and freq of naïve CD8+ T-cells, which was not seen with CMVneg donors. This suggests that seropositivity sets the abs and freq of CD8 subpopulations near to a decisive cutoff for the development of GVHD. Conversely, other factors influences the development of GVHD in those patients whose donors were seronegative. In other words, seropositivity of the donor affects the graft composition and thus the risk of GVHD. Finally, our data indicate that a higher proportion of naïve or central memory CCR7+ CD4+ T cells in the donor graft could prevent CMV reactivation suggesting that graft composition affects also CMV reactivation. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
29. 39 Phytochemical indole-3-carbinol synergizes strongly with fludarabine and induces p53-dependent and -independent cell death in chronic lymphocytic leukemia cells irrespective of their IGHV mutation state and treatment resistances
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Cecilia Muñoz-Calleja, Juan M. Zapata, Ismael Buño, Carolina Martínez-Laperche, Beatriz Somovilla-Crespo, Gema Perez-Chacon, and Nerea Rebolleda
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Cancer Research ,Mutation ,Programmed cell death ,Chronic lymphocytic leukemia ,Biology ,medicine.disease_cause ,medicine.disease ,Fludarabine ,chemistry.chemical_compound ,Oncology ,Phytochemical ,chemistry ,Immunology ,medicine ,Cancer research ,Indole-3-carbinol ,IGHV@ ,medicine.drug - Published
- 2014
30. Serum interleukin-8 and its relationship to tumor burden and treatment response across malignancies of multiple tissue origins
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Inmaculada Rodriguez, Ignacio Melero, Carmen Oñate, José María López-Picazo, Salvador Martín-Algarra, Bruno Sangro, Stefanie Gross, Jose Luis Perez-Gracia, Alvaro Gonzalez, Cecilia Muñoz-Calleja, Maria A Rodriguez, Omar Carranza-Rua, Guiomar Perez, Sara Fernández-Landázuri, Carlos Alfaro, and Miguel F. Sanmamed
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Cancer Research ,Treatment response ,Chemokine ,biology ,Multiple cancer ,business.industry ,Tumor burden ,Inflammation ,Tumor M2-PK ,Oncology ,Immunology ,biology.protein ,Malignant cells ,Medicine ,Interleukin 8 ,medicine.symptom ,business - Abstract
e22135 Background: IL-8 is a chemokine that is produced by malignant cells of multiple cancer types and that exerts various functions in shaping pro-tumoral vascularization and inflammation/immunit...
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- 2014
31. NK-Cells In Dasatinib-Treated Chronic Myeloid Leukemia Patients Display a Unique Phenotype Associated With Cytotoxic Potential
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Anna Kreutzman, Cecilia Muñoz Calleja, Begoña Maestro Gutiérrez, Maria José Requena Rodríguez, Valentin Garcia, Raúl Córdoba Mascuñano, Juan Luis Steegmann, and Beatriz Colom Fernandez
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education.field_of_study ,business.industry ,medicine.drug_class ,Immunology ,Population ,Myeloid leukemia ,Imatinib ,C-C chemokine receptor type 7 ,Cell Biology ,Hematology ,NKG2D ,Biochemistry ,Tyrosine-kinase inhibitor ,Dasatinib ,Nilotinib ,Medicine ,business ,education ,medicine.drug - Abstract
Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI), which is used successfully in the treatment of chronic myeloid leukemia (CML). Dasatinib has two unique features when compared to other TKIs (imatinib, nilotinib); first, dasatinib has a significantly shorter half-life in the plasma and second, dasatinib inhibits a wider spectrum of kinases, including several kinases known to be important in the function of the immune system (src, tec, and syk families), which are not affected by the other TKIs. Interestingly, it has been recently shown that both short-term exposure to dasatinib in vivo and long-term treatment with dasatinib improves NK-cell cytotoxicity, however, the mechanisms are not known. To study the improved cytotoxicity observed in dasatinib-treated patients, we aimed to perform a complete NK-cell phenotyping in these patients. Finally, our goal is to correlate NK-cell phenotype with NK-cell cytotoxicity, and to study the possible correlation between phenotypical changes, NK-cell function and clinical outcome. Methods This study included 19 dasatinib-treated (DA) CML patients, both first-line (n=7) and second-line (n=12). To investigate the specificity of the immunomodulatory effects of dasatinib, a control group of 9 CML patients treated with imatinib (IM) and another group of 12 healthy donors (HD) were included. Peripheral blood samples obtained before the patients took their daily drug dose were phenotyped with a comprehensive 8-color flow cytometry panel (total 32 antibodies, table 1). To study the correlation between phenotypical changes and NK-cell cytotoxicity, we performed a standard CD107 degranulation assay. Mononuclear cells were incubated for 6 hours in the presence of the target cell line K562 and a CD107 antibody. CD107 positive NK-cells were then phenotyped with the same panel of 32 antibodies. Results All results are summarized in table 1. In brief, DA- and IM-treated CML patients and HD had equal proportions of NK-cells (CD3negCD56+) of total lymphocytes. Regarding trafficking molecules, NK-cells in both DA- and IM-patients had a lower frequency of the chemokine receptor CCR7 when compared to HD. This suggests a reduction in the NK-cell population that is able to migrate to lymph nodes, and is likely caused by the disease or TKIs in general. Moreover, DA-treatment specifically decreases the expression of the homing molecule CD62L in NK-cells. In addition, NK-cells in DA-patients, when compared to IM and HD, expressed less CD11b and significantly more often CD11c and HLA-DR, which reproduce the immunophenotypic changes that typically occurs in recently activated NK-cells and has been shown to associate with improved clinical benefits. Conversely, increased expression of CD57 together with a lower frequency of CD27 and CD28 were observed in both groups of patients and were similar to those typically observed in conditions of chronic NK-cell stimulation. In contrast, DA-patients had a lower frequency of most of the studied NK-receptors (Nkp30, Nkp46, NKG2D, CD94, CD161, KIR2DL1/S1) when compared to IM and HD. This suggests that NK-cells in DA-treated patients have a more mature phenotype, which is caused by the treatment. Conclusions NK-cells in TKI-treated CML patients display a mature phenotype, which is often observed after chronic stimulation suggesting that TKIs have immunomodulatory effects on NK-cells or the disease itself causes the changes. Interestingly, NK-cells in DA-treated patients express a highly differentiated phenotype characterized by high expression of CD57, and decreased expression of Nkp30, Nkp46 and CD161. Similar changes were not seen in IM-patients or HD. It is possible that NK-cells expressing this phenotype might also represent those NK-cells that have previously been driven into clonal expansion by encounters with pathogens because of the specific immunomodulatory effects of dasatinib. This phenotype of highly mature NK-cells, which is associated with high cytolytic potential, could be responsible for the previously described enhanced NK-cytotoxicity caused by dasatinib. In accordance, our preliminary results suggest that these unique phenotypic changes observed in DA-treated patients correlates with the cytotoxic potential. Studies to correlate these results with therapy outcome are ongoing. Disclosures: Garcia: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Research Funding. Steegmann:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau.
- Published
- 2013
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