Olagüe, C. (Cristina)
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- Photodynamic nasal SARS-CoV-2 decolonization shortens infectivity and influences specific T-Cell responses.(Frontiers, 2023) Moreno-Galarraga, L. (Laura); Martin-Navarro, L. (Loreto); González-Aseguinolaza, G. (Gloria); Muñoz-Rodríguez, N. (Natalia); Pineda-Lucena, A. (Antonio); Olagüe, C. (Cristina); Pina-Sanchez, M. (Manuel); Camps, G. (Gracian); Rua, M. (Marta); Smerdou, C. (Cristian); Pozo, J.L. (José Luis) del; Pozuelo, M. (Marta); Zuaznabar, J. (Jon); Rodriguez, J.A. (José Antonio); Carmona-Torre, F. (Francisco de A.); Fernandez-Montero, A. (Alejandro); Zazpe, J. (Jon); Reina, G. (Gabriel); Kolenda, J. (Jack); Marchese, F.P. (Francesco P.); Quiroga, J. (Jorge); Martínez-Fernández, M. (Maria); Argemí, J. (Josepmaria); Pastrana, M. (Marta); Maestro, S. (Sheila)Background: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a b-coefficient of -812.2 (CI95%= -478660 – -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.
- Identification of CD4+ and CD8+ T cell epitopes of woodchuck hepatitis virus core and surface antigens in BALB/c mice(Elsevier, 2010) González-Aseguinolaza, G. (Gloria); Vales, A. (África); Olagüe, C. (Cristina); Otano, I. (Itziar); Menne, S. (Stephan); Ochoa, L. (Laura); Prieto, J. (Jesús); Sarobe, P. (Pablo); Lasarte, J.J. (Juan José)A therapeutic vaccine against chronic hepatitis B virus (HBV) infection requires the development of a strong and multispecific Th1 cell immune response. Woodchucks chronically infected with the woodchuck hepatitis virus (WHV) closely resemble HBV infection and represent the best animal model for this hepadnavirus-induced disease. Using the BIMAS "HLA Peptide Binding Predictions" program, we have identified and further characterized novel H-2(d)-restricted CD8+ epitopes within the WHV core (peptides C#12-21, C#18-32, C#19-27, C#61-69) and surface antigens (peptides preS2#10-18, preS2#27-35, S#76-84, S#133-140 and S#257-265), respectively. These peptides bind to H-2(d) with high efficiency and upon immunization of mice with peptide and Freund's adjuvant they induce the development of IFN-gamma producing T cells. More importantly, WHV core peptides C#19-27 and C#61-69 and WHV surface peptides S#133-140 and S#257-265 were also recognized by CD8+ T cells after immunization of mice with DNA/PEI nanoparticles. Direct stimulation of splenocytes obtained from such DNA-immunized mice with peptides C#18-32, S#76-84, and S#257-265 resulted in significant production of IFN-gamma. Thus, we have identified T cell determinants in mice from WHV core and surface antigens that have important value for designing and evaluating an effective vaccine against hepadnavirus infection.
- Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors(American Society of Clinical Oncology, 2004) Benito-Boilos, A. (Alberto); Mazzolini, G. (Guillermo); Lacasa, C. (Carlos); Olagüe, C. (Cristina); Herraiz-Bayod, M.J. (Maite J.); Qian, C. (Cheng); Subtil, J.C. (José Carlos); Sola, J. (Josu); Sangro, B. (Bruno); Larrache, J. (Javier); Melero, I. (Ignacio); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Sadaba, B. (Belén); Quiroga, J. (Jorge); Ruiz, J. (Juan); Pueyo, J. (Jesús)PURPOSE: To evaluate the feasibility and safety of intratumoral injection of an adenoviral vector encoding human interleukin-12 genes (Ad.IL-12) and secondarily, its biologic effect for the treatment of advanced digestive tumors. PATIENTS AND METHODS: Ad.IL-12 was administered in doses ranging from 2.5 x 10(10) to 3 x 10(12) viral particles, to seven cohorts of patients with advanced pancreatic, colorectal, or primary liver malignancies. Patients were thoroughly assessed for toxicity, and antitumor response was evaluated by imaging techniques, tumor biopsy, and hypersensitivity skin tests. Patients with stable disease and no serious adverse reactions were allowed to receive up to 3 monthly doses of Ad.IL-12. RESULTS: Twenty-one patients (nine with primary liver, five with colorectal, and seven with pancreatic cancers) received a total of 44 injections. Ad.IL-12 was well tolerated, and dose-limiting toxicity was not reached. Frequent but transient adverse reactions, including fever, malaise, sweating, and lymphopenia, seemed to be related to vector injection rather than to transgene expression. No cumulative toxicity was observed. In four of 10 assessable patients, a significant increase in tumor infiltration by effector immune cells was apparent. A partial objective remission of the injected tumor mass was observed in a patient with hepatocellular carcinoma. Stable disease was observed in 29% of patients, mainly those with primary liver cancer. CONCLUSION: Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.
- Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas.(American Society of Clinical Oncology, 2005) Lucena-Ramírez, J.F. (Juan Felipe); Benito-Boilos, A. (Alberto); Mazzolini, G. (Guillermo); Alfaro, C. (Carlos); Olagüe, C. (Cristina); Herraiz-Bayod, M.J. (Maite J.); Qian, C. (Cheng); Subtil, J.C. (José Carlos); Sola, J. (Josu); Sangro, B. (Bruno); Melero, I. (Ignacio); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Sadaba, B. (Belén); Bendandi, M. (Maurizio); Tirapu, I. (Íñigo); Quiroga, J. (Jorge); Ruiz, J. (Juan); Feijoo, E. (Esperanza); Arina, A. (Ainhoa)PURPOSE: To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity. PATIENTS AND METHODS: Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals. RESULTS: Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment. CONCLUSION: Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.
- IL12-mediated liver inflammation reduces the formation of AAV transcriptionally active forms but has no effect over preexisting AAV transgene expression(Public Library of Science, 2013) González-Aseguinolaza, G. (Gloria); Gil-Fariña, I. (Irene); High, K.A. (Katherine A.); Vales, A. (África); Olagüe, C. (Cristina); Prieto, J. (Jesús); Vanrell, L. (Lucía); Scala, M. (Marianna) Di; Mingozzi, F. (Federico)Recombinant adenoassociated viral vectors (rAAV) have proven to be excellent candidates for gene therapy clinical applications. Recent results showed that cellular immunity to AAV represents a major challenge facing the clinical use of systemic administration of these vectors. Interestingly, no preclinical animal model has previously fully reproduced the clinical findings. The aim of the present work was to enhance the T cell immune response against AAV capsid in mice by the administration of a rAAV expressing the immunostimulatory cytokine IL-12. Our results indicate that although IL-12 expression enhanced the AAV capsid-specific immune response it failed to eliminate transduced hepatocytes and long-term expression was achieved. We found that AAV-mediated transgene expression is altered by IL-12-induced liver inflammation. However, IL-12 expression has no effect over preexisting AAV-mediated transgene expression. IL-12 down-regulates AAV mediated transgene expression via induction of IFN-γ production by NK and T cells, but without altering the transduction efficiency measured by viral genomes. Our results indicate that liver inflammation affects the formation of transcriptionally active AAV vector genomes through an unknown mechanism that can be avoided by the use of DNA-demethylating or anti-inflammatory agents.
- TMEM173 alternative spliced isoforms modulate viral replication through STING pathway(American Association of Immunologists, 2018) Rodríguez-García, E. (Estefanía); Ferrero, R. (Roberto); González-Aseguinolaza, G. (Gloria); Ríus-Rocabert, S. (Sergio); Olagüe, C. (Cristina); Larrea, E. (Esther); Nistal-Villan, E. (Estanislao); Prieto, J. (Jesús); Fortes, P. (Puri); Llorens, C. (Carles)The innate immune system provides a primary line of defense against pathogens. Stimulator of IFN genes (STING), encoded by the TMEM173 gene, is a critical protein involved in IFN-b induction in response to infection by different pathogens. In this study, we describe the expression of three different alternative-spliced human (h) TMEM173 mRNAs producing STING truncated isoforms 1, 2, and 3 in addition to the full-length wild-type (wt) hSTING. All of the truncated isoforms lack exon 7 and share the N-terminal transmembrane region with wt hSTING. Overexpression of the three STING truncated isoforms failed to induce IFN-b, and they acted as selective pathway inhibitors of wt hSTING even in combination with upstream inducer cyclic-di-GMP-AMP synthase. Truncated isoforms alter the stability of wt hSTING, reducing protein t1/2 to some extent by the induction of proteasome-dependent degradation. Knocking down expression of truncated isoforms increased production of IFN-b by THP1 monocytes in response to intracellular cytosolic DNA or HSV-1 infection. At early stages of infection, viruses like HSV-1 or vesicular stomatitis virus reduced the ratio of full-length wt hSTING/truncated STING isoforms, suggesting the skewing of alternative splicing of STING toward truncated forms as a tactic to evade antiviral responses. Finally, in silico analysis revealed that the human intron–exon gene architecture of TMEM173 (splice sites included) is preserved in other mammal species, predominantly primates, stressing the relevance of alternative splicing in regulating STING antiviral biology.