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1.
Proc Natl Acad Sci U S A ; 121(10): e2313681121, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38408238

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron strain has evolved into highly divergent variants with several sub-lineages. These newly emerging variants threaten the efficacy of available COVID-19 vaccines. To mitigate the occurrence of breakthrough infections and re-infections, and more importantly, to reduce the disease burden, it is essential to develop a strategy for producing updated multivalent vaccines that can provide broad neutralization against both currently circulating and emerging variants. We developed bivalent vaccine AdCLD-CoV19-1 BA.5/BA.2.75 and trivalent vaccines AdCLD-CoV19-1 XBB/BN.1/BQ.1.1 and AdCLD-CoV19-1 XBB.1.5/BN.1/BQ.1.1 using an Ad5/35 platform-based non-replicating recombinant adenoviral vector. We compared immune responses elicited by the monovalent and multivalent vaccines in mice and macaques. We found that the BA.5/BA.2.75 bivalent and the XBB/BN.1/BQ.1.1 and XBB.1.5/BN.1/BQ.1.1 trivalent vaccines exhibited improved cross-neutralization ability compared to their respective monovalent vaccines. These data suggest that the developed multivalent vaccines enhance immunity against circulating Omicron subvariants and effectively elicit neutralizing antibodies across a broad spectrum of SARS-CoV-2 variants.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Animales , Humanos , Ratones , Vacunas contra la COVID-19/genética , COVID-19/prevención & control , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Macaca , Vacunas Combinadas , Anticuerpos Antivirales
2.
Proc Natl Acad Sci U S A ; 120(9): e2213793120, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36802434

RESUMEN

Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRß-deficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRß-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/ß-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3ß-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.


Asunto(s)
Células T Auxiliares Foliculares , Linfocitos T Colaboradores-Inductores , Ratones , Humanos , Animales , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Centro Germinal , Factor 1 de Transcripción de Linfocitos T/genética , Diferenciación Celular
3.
FASEB J ; 34(3): 4462-4481, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31989715

RESUMEN

Myeloid progenitor cells have generally been considered the predominant source of myeloid cells under steady-state conditions. Here we show that NK cells contributed to a myeloid cell lineage pool in naïve and tumor-bearing mice. Using fate tracing of NKp46+ cells, we found that myeloid cells could be derived from NK cells. Notably, among mature CD11b+ CD27+ NK cells, c-Kit+ CD24+ NK cells were capable of differentiating into a range of myeloid lineages in vitro and produced neutrophils and monocytes in vivo. The differentiation was completely inhibited by NK-stimulating cytokines. In addition to the potential for differentiation into myeloid cells, c-Kit+ CD24+ NK cells retained NK cell phenotypes and effector functions. Mechanistically, GATA-2 was necessary for the differentiation of c-Kit+ CD24+ NK cells. Therefore, we discovered that GATA-2-dependent differentiation of c-Kit+ CD24+ NK cells contributes to myeloid cell development and identified a novel pathway for myeloid lineage commitment under physiological conditions.


Asunto(s)
Proliferación Celular/fisiología , Células Mieloides/citología , Células Mieloides/metabolismo , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Antígeno CD24/genética , Antígeno CD24/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Lentivirus/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Monocitos/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/genética , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Neutrófilos/metabolismo , Fagocitosis/genética , Fagocitosis/fisiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ARN , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
4.
J Immunol ; 201(4): 1287-1294, 2018 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-29987162

RESUMEN

Secretory IgA is a key host defense mechanism that controls the intestinal microbiota. We investigated the role of CD11c+CX3CR1+CD64+ macrophages in IgA production in the intestine. Intestinal CX3CR1+ macrophages directly induced IgA secretion by B cells. Ag delivery to lamina propria (LP) CX3CR1+ macrophages specifically induced intestinal IgA production. The induction of IgA by CX3CR1+ macrophages required BAFF, a proliferation-inducing ligand, and TNF-α, but was surprisingly independent of TLR-mediated microbial recognition and retinoic acid signaling. IgA secretion by CX3CR1+ macrophages was enhanced by LP CD8+ T cells through the secretion of IL-9 and IL-13. CX3CR1+ macrophages and CD8+ T cells induced IgA production by B cells independently of mesenteric lymph nodes and Peyer patches. Our data reveal a previously unrecognized cellular circuitry in which LP CX3CR1+ macrophages, B cells, and CD8+ T cells coordinate the protective Ig secretion in the small intestine upon peripheral Ag delivery.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunoglobulina A Secretora/biosíntesis , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Animales , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Receptor 1 de Quimiocinas CX3C/inmunología , Inmunidad Mucosa/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
5.
J Allergy Clin Immunol ; 142(2): 530-541.e6, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29038008

RESUMEN

BACKGROUND: Inhaled protease allergens preferentially trigger TH2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2-favorable DCs in the airway remains unclear. OBJECTIVE: We sought to determine a subset of DCs responsible for TH2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway. METHODS: Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies. RESULTS: Protease allergens induced a remarkable accumulation of TH2-favorable programmed cell death 1 ligand 2 (PD-L2)+ DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2+ DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2+ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2+ DC population in mice lacking mast cells. CONCLUSION: Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of TH2-favorable PD-L2+ DCs in allergic asthma and suggest that targeting the PD-L2+ DC pathway might be effective in suppressing allergic T-cell responses in the airway.


Asunto(s)
Asma/inmunología , Células Dendríticas/inmunología , Fibrinógeno/metabolismo , Hipersensibilidad/inmunología , Fragmentos de Péptidos/metabolismo , Péptido Hidrolasas/metabolismo , Receptor Toll-Like 4/metabolismo , Alérgenos/inmunología , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Fibrinógeno/inmunología , Humanos , Inmunidad Innata , Interleucina-13/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fragmentos de Péptidos/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Células Th2/inmunología , Receptor Toll-Like 4/genética
6.
Cytotherapy ; 19(1): 119-127, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27864016

RESUMEN

BACKGROUND AIMS: Dendritic cells are well known as the most potent antigen-presenting cells. Nonetheless, their use in immunotherapy has been limited by the time-consuming and laborious steps involved in their generation in vitro. Therefore, much attention has been placed on alternative antigen-presenting cells that are relatively more convenient to manipulate. METHODS: In this study, the efficacy of B cells as antigen-presenting cells, compared with dendritic cells, in the induction of cytotoxic T lymphocytes against cytomegalovirus-specific antigens was evaluated. B cells were isolated from the peripheral blood mononuclear cells of healthy individuals, loaded with α-galactosylceramide for activation, and nucleofected with cytomegalovirus-antigen coding plasmid DNA. Antigen-nucleofected B cells or dendritic cells were cocultured with T cells for 14 days in vitro. RESULTS: The proliferation of cytotoxic T lymphocytes induced by B cells was similar to that of those induced by dendritic cells. Additionally, the immunogenicity of both sets of cytotoxic T lymphocytes was similar not only in interferon-γ enzyme-linked immunospot assays but also in cytotoxicity assays. DISCUSSION: These observations suggest that α-galactosylceramide-loaded B cells could be used as antigen-presenting cells as an alternative to dendritic cells. Using B cells has several benefits, including cost-effectiveness and being both less time-consuming and less labor-intensive.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T Citotóxicos/inmunología , Antígenos Virales/genética , Células Cultivadas , Citomegalovirus/inmunología , Células Dendríticas/inmunología , Ensayo de Immunospot Ligado a Enzimas/métodos , Galactosilceramidas/farmacología , Humanos , Interferón gamma/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Activación de Linfocitos
7.
Mediators Inflamm ; 2016: 3472608, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27445434

RESUMEN

The prevalence of allergic disorders including atopic dermatitis (AD) and food allergy (FA) has increased dramatically in pediatric populations, but there is no effective drug available for their management. Therefore, trials are required for the development of safe therapeutic agents such as herbal medicines. We determined whether orally administered Poria cocos bark (PCB) extract could exert immunosuppressive effects on allergic and inflammatory symptoms of AD and FA. For both AD, which was induced using house dust mite extract, and FA, which was induced by exposure to ovalbumin, model mice were orally treated with PCB extract for 62 days and 18 days, respectively. We also investigated the inductive effect of PCB extract on the generation and maintenance of Foxp3(+)CD4(+) regulatory T cells (Tregs). The symptoms of AD and FA were ameliorated by the administration of PCB extract. Furthermore, PCB extract inhibited the Th2-related cytokines and increased the population of Foxp3(+)CD4(+) Tregs in both AD and FA models. In ex vivo experiments, PCB extract promoted the functional differentiation of Foxp3(+)CD4(+) Tregs, which is dependent on aryl hydrocarbon receptor activation. Thus, PCB extract has potential as an oral immune suppressor for the treatment of AD and FA through the generation of Tregs.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Extractos Vegetales/uso terapéutico , Wolfiporia/química , Animales , Linfocitos T CD4-Positivos/metabolismo , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad a los Alimentos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Ratones , Ratones Endogámicos BALB C , Corteza de la Planta , Linfocitos T Reguladores/efectos de los fármacos
8.
Int J Cancer ; 136(11): 2579-87, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25379865

RESUMEN

Carcinoembryonic antigen (CEA) is a well-known tumor antigen that is found in the serum of patients with various cancers and is correlated with an increased risk of cancer recurrence and metastasis. To understand the tumor environment and to develop antitumor therapies, CEA has been studied as an antigen to activate/tolerate specific T cells. In this study, we show that CEA can function as a coinhibitory molecule and can inhibit the activation of human peripheral blood mononucleated cell-derived T cells. The addition of CEA-overexpressing tumor cells or immobilized CEA dampened both cell proliferation and the expression of IL-2 and CD69 expression in T cells after TCR stimulation. The phosphorylation of ERK and translocation of NFAT were hampered in these cells, whereas the phosphorylation of proximal TCR signaling molecules such as ZAP70 and phospholipase Cγ was not affected by immobilized CEA. To determine the relevance of carcinoembryonic antigen-related cell adhesion molecule-1 and Src homology region 2 domain-containing phosphatase (SHP) molecules to CEA-mediated suppression, we tested the effect of the SHP inhibitor, NSC-87877, on CEA-mediated suppression of T cells; however, it did not reverse the effect of CEA. Collectively, these results indicate that CEA can function as a modulator of T-cell responses suggesting a novel mechanism of tumor evasion.


Asunto(s)
Antígeno Carcinoembrionario/metabolismo , Tolerancia Inmunológica , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular , Proliferación Celular , Regulación de la Expresión Génica , Células HeLa , Humanos , Activación de Linfocitos , Neoplasias/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos
9.
Eur J Immunol ; 44(6): 1672-84, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24659444

RESUMEN

Myeloid-derived suppressor cells (MDSCs), which suppress diverse innate and adaptive immune responses and thereby provide an evasion mechanism for tumors, are emerging as a key population linking inflammation to cancer. Although many inflammatory factors that induce MDSCs in the tumor microenvironment are known, the crucial components and the underlying mechanisms remain elusive. In this study, we proposed a novel mechanism by which serum amyloid A3 (SAA3), a well-known inflammatory factor, connects MDSCs with cancer progression. We found that SAA3 expression in BALB/c mice increased in monocytic MDSCs (Mo MDSCs) with tumor growth. The induction of SAA3 by apo-SAA treatment in Mo MDSCs enhanced their survival and suppressive activity, while it inhibited GM-CSF-induced differentiation. Endogenous SAA3 itself contributed to the increase in the survival and suppressive activity of Mo MDSCs. We demonstrated that SAA3 induced TLR2 signaling, in turn increasing the autocrine secretion of TNF-α, that led to STAT3 activation. In addition, activated STAT3 enhanced the suppressive activity of Mo MDSCs. Furthermore, SAA3 induction in Mo MDSCs contributed to accelerating tumor progression in vivo. Collectively, these data suggest a novel mechanism by which Mo MDSCs mediate inflammation through SAA3-TLR2 signaling and thus exacerbate cancer progression by a STAT3-dependent mechanism.


Asunto(s)
Células Mieloides/inmunología , Neoplasias Experimentales/inmunología , Factor de Transcripción STAT3/inmunología , Proteína Amiloide A Sérica/inmunología , Receptor Toll-Like 2/inmunología , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Células Mieloides/patología , Neoplasias Experimentales/patología , Transducción de Señal/inmunología
10.
J Immunol ; 188(9): 4226-34, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22474024

RESUMEN

Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Tolerancia Inmunológica , Células Mieloides/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/inmunología , Proteínas de Unión a Tacrolimus/inmunología , Animales , Arginasa/biosíntesis , Arginasa/inmunología , Proliferación Celular , Ratones , Ratones Endogámicos BALB C , Células Mieloides/metabolismo , Células Mieloides/patología , FN-kappa B/inmunología , FN-kappa B/metabolismo , Proteínas de Neoplasias/biosíntesis , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/inmunología , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Proteínas de Unión a Tacrolimus/biosíntesis , Factores de Tiempo
11.
Immune Netw ; 24(1): e2, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38455465

RESUMEN

Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.

12.
Cancer Res Treat ; 56(1): 208-218, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37402409

RESUMEN

PURPOSE: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment. Patients were administered low (2.5×107 cells/dose), medium (5.0×107 cells/dose), or high dose (1.0×108 cells/dose) of BVAC-B intravenously four times every 4 weeks. Primary endpoints included safety and maximum tolerated BVAC-B dose. Secondary endpoints included preliminary clinical efficacy and BVAC-B-induced immune responses. RESULTS: Eight patients were treated with BVAC-B at low (n=1), medium (n=1), and high doses (n=6). No dose-limiting toxicity was observed, while treatment-related adverse events (TRAEs) were observed in patients treated with medium and high doses. The most common TRAEs were grade 1 (n=2) and grade 2 (n=2) fever. Out of the six patients treated with high-dose BVAC-B, three had stable disease with no response. Interferon gamma, tumor necrosis factor-α, and interleukin-6 increased after BVAC-B treatment in all patients with medium and high dose, and HER2-specific antibody was detected in some patients. CONCLUSION: BVAC-B monotherapy had a safe toxicity profile with limited clinical activity; however, it activated immune cells in heavily pretreated patients with HER2-positive gastric cancer. Earlier treatment with BVAC-B and combination therapy is warranted for evaluation of clinical efficacy.


Asunto(s)
Neoplasias Gástricas , Vacunas , Humanos , Trastuzumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Monocitos/patología , Vacunas/uso terapéutico , Inmunoterapia
13.
Int J Antimicrob Agents ; 63(3): 107082, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38163552

RESUMEN

Global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron subvariants, such as BA.4, BA.5 and XBB.1.5, has been leading the recent wave of coronavirus disease 2019 (COVID-19). Unique mutations in the spike proteins of these emerging Omicron subvariants caused immune evasion from the pre-existing protective immunity induced by vaccination or natural infection. Previously, we developed AdCLD-CoV19-1, a non-replicating recombinant adenoviral vector that encodes the receptor binding domain of the spike protein of the ancestral SARS-CoV-2 strain. Based on the same recombinant adenoviral vector platform, updated vaccines that cover unique mutations found in each Omicron subvariant, including BA.1, BA.2, BA.4.1 and BA.5, were constructed. Preclinical studies revealed that each updated vaccine as a booster shot following primary vaccination targeting the ancestral strain improved neutralizing antibody responses against the pseudovirus of its respective strain most effectively. Of note, boosting with a vaccine targeting the BA.1 or BA.2 Omicron subvariant was most effective in neutralization against the pseudovirus of the BA.2.75 strain, whereas BA.4.1/5-adapted booster shots were most effective in neutralization against the BQ.1, BQ1.1 and BF.7 strains. Therefore, it is imperative to develop a vaccination strategy that can cover the unique spike mutations of currently circulating Omicron subvariants in order to prevent the next wave of COVID-19.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Ratones , SARS-CoV-2/genética , COVID-19/prevención & control , Anticuerpos Neutralizantes , Vectores Genéticos , Adenoviridae/genética
14.
Front Immunol ; 15: 1371353, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38605958

RESUMEN

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.


Asunto(s)
Vacunas contra el Cáncer , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Papillomavirus Humano 16 , Recurrencia Local de Neoplasia/patología , Vacunas contra el Cáncer/efectos adversos
15.
Int J Cancer ; 132(12): 2839-48, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23184679

RESUMEN

Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88(-/-) mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88(-/-) mice than in wild-type mice. Although the generation of CD11b(+) Gr-1(+) MDSCs was less in Myd88(-/-) mice than in wild-type mice, Myd88(-/-) mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88(-/-) mice failed to suppress antigen-specific proliferation of CD8(+) T cells and CD4(+) T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88(-/-) mice compared with wild-type mice after tumor challenge. Furthermore, CD4(+) T cells residing in tumor-draining lymph nodes of Myd88(-/-) mice secreted more TNF-α than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.


Asunto(s)
Células Mieloides/inmunología , Células Mieloides/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Transducción de Señal , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Terapia de Inmunosupresión , Ratones , Factor 88 de Diferenciación Mieloide/antagonistas & inhibidores , Factor 88 de Diferenciación Mieloide/genética , Neoplasias/genética , Neoplasias/patología , Factor de Necrosis Tumoral alfa/metabolismo
16.
Eur J Immunol ; 42(10): 2564-73, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22740051

RESUMEN

Wnt/ß-catenin signaling plays a crucial role during embryogenesis and tumorigenesis, and in T cells, promotes the differentiation of Th2 cells. However, the role of Wnt signals in the differentiation and maintenance of human Th17 cells remains poorly understood. We found that the higher levels of IL-17 in the synovial fluid of rheumatoid arthritis (RA) patients compared with that of osteoarthritis (OA) patients were associated with a higher concentration of sFRP1 (secreted Frizzled-Related Protein 1), an inhibitor of the Wnt/ß-catenin pathway. The addition of sFRP1 during TCR-mediated stimulation induced a significant increase in IL-17 production by both naïve and memory CD4(+) T cells. Moreover, under Th17-differentiation conditions, the addition of sFRP1 significantly reduced the requirement for TGF-ß. Mechanistically, we observed that sFRP1 significantly enhanced the phosphorylation of Smad2/3 in CD4(+) T cells upon TGF-ß stimulation and that blocking TGF-ß signaling abolished the Th17-promoting activity of sFRP1. Our findings reveal a novel function for sFRP1 as a potent inducer of human Th17-cell differentiation. Consequently, sFRP1 may represent a promising target for the treatment of Th17-mediated disease in humans.


Asunto(s)
Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas de Ciclo Celular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-17/inmunología , Proteínas de la Membrana/metabolismo , Células Th17/inmunología , Diferenciación Celular , Células Cultivadas , Humanos , Memoria Inmunológica , Fosforilación , Proteína Smad2/metabolismo , Membrana Sinovial/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Vía de Señalización Wnt/inmunología
17.
Eur J Immunol ; 42(7): 1685-94, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22585464

RESUMEN

Retinoic acid (RA) is a diverse regulator of immune responses. Although RA promotes natural killer T (NKT) cell activation in vitro by increasing CD1d expression on antigen-presenting cells (APCs), the direct effects of RA on NKT-cell responses in vivo are not known. In the present study, we demonstrated the effect of RA on the severity of Con A-induced hepatitis and molecular changes of NKT cells. First, we demonstrated that Con A-induced liver damage was ameliorated by RA. In correlation with cytokine levels in serum, RA regulated the production of IFN-γ and IL-4 but not TNF-α by NKT cells without influencing the NKT-cell activation status. However, RA did not alleviate α-GalCer-induced liver injury, even though it reduced IFN-γ and IL-4 but not TNF-α levels in serum. This regulation was also detected when liver mononuclear cells (MNCs) or NKT hybridoma cells were treated with RA in vitro. The regulatory effect of RA on NKT cells was mediated by RAR-α, and RA reduced the phosphorylation of MAPK. These results suggest that RA differentially modulates the production of effector cytokines by NKT cells in hepatitis, and the suppressive effect of RA on hepatitis varies with the pathogenic mechanism of liver injury.


Asunto(s)
Hepatitis/tratamiento farmacológico , Hepatitis/inmunología , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Tretinoina/farmacología , Animales , Western Blotting , Concanavalina A/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Galactosilceramidas/administración & dosificación , Regulación de la Expresión Génica/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Estimación de Kaplan-Meier , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , ARN/química , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Ácido Retinoico/inmunología , Receptor alfa de Ácido Retinoico , Organismos Libres de Patógenos Específicos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
18.
Proc Natl Acad Sci U S A ; 107(19): 8742-7, 2010 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-20421479

RESUMEN

Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3(+) T cells by TGF-beta when stimulated in the presence of all-trans retinoic acid and rapamycin. The "converted" Foxp3(+) T cells that were derived from Th2 memory cells down-regulated GATA-3 and IRF4 and produced little IL-4, IL-5, and IL-13. Instead, the converted Foxp3(+) T cells suppressed the proliferation and cytokine production of Th2 memory cells. More importantly, the converted Foxp3(+) T cells efficiently accumulated in the airways and significantly suppressed Th2 memory cell-mediated airway hyperreactivity, eosinophilia, and allergen-specific IgE production. Our findings reveal the plasticity of Th2 memory cells and provide a strategy for adoptive immunotherapy for the treatment of allergic diseases.


Asunto(s)
Asma/inmunología , Factores de Transcripción Forkhead/inmunología , Memoria Inmunológica/inmunología , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Animales , Asma/complicaciones , Asma/fisiopatología , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/inmunología , Citocinas/metabolismo , Eosinófilos/inmunología , Eosinófilos/patología , Epítopos/inmunología , Femenino , Factor de Transcripción GATA3/metabolismo , Memoria Inmunológica/efectos de los fármacos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Pruebas de Neutralización , Sirolimus/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patología , Células Th2/efectos de los fármacos , Células Th2/patología , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/farmacología
19.
Int J Cancer ; 131(3): 741-51, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-21898392

RESUMEN

Myeloid-derived suppressor cells (MDSCs), which accumulate during tumor progression, have been shown to function as important suppressor cells. In a previous study, we showed that immunosuppressive MDSCs could function as immunogenic antigen-presenting cells (APCs) with the help of activated natural killer T (NKT) cells. In the current study, however, we found that MDSCs harvested at a late time point after tumor injection (late MDSCs) were poorly immunogenic even when stimulated with activated NKT cells. As tumor growth progressed, the expression of MHC and costimulatory molecules on MDSCs was gradually down-regulated. Late MDSCs also had innate defects in activation and differentiation mediated by cytokine stimuli. Although late MDSCs treated only with all-trans-retinoic acid (ATRA), a stimulating agent for MDSC differentiation, could not become immunogenic, NKT ligand-loaded, ATRA-treated late MDSCs could be converted into immunogenic APCs to induce incremental immune responses. Furthermore, these effects were mediated by NKT cells secreting IFNγ, and ATRA-mediated increases in glutathione (GSH) levels. Thus, combined treatment with differentiating and activating agents is a prerequisite for the conversion of late MDSCs into immunogenic APCs. Collectively, these results suggest that combined treatments are required for the differentiation and activation of late MDSCs in late stage cancer.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Células Mieloides/inmunología , Células T Asesinas Naturales/inmunología , Neoplasias/inmunología , Tretinoina/farmacología , Animales , Presentación de Antígeno , Diferenciación Celular , Línea Celular Tumoral , Glutatión/metabolismo , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Mieloides/efectos de los fármacos , Neoplasias/metabolismo , Neoplasias/patología
20.
Vaccines (Basel) ; 10(5)2022 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-35632468

RESUMEN

Several COVID-19 platforms have been licensed across the world thus far, but vaccine platform research that can lead to effective antigen delivery is still ongoing. Here, we constructed AdCLD-CoV19 that could modulate humoral immunity by harboring SARS-CoV-2 antigens onto a chimeric adenovirus 5/35 platform that was effective in cellular immunity. By replacing the S1/S2 furin cleavage sequence of the SARS-CoV-2 Spike (S) protein mounted on AdCLD-CoV19 with the linker sequence, high antigen expression was confirmed in various cell lines. The high levels of antigen expression contributed to antigen-specific antibody activity in mice and non-human primates (NHPs) with a single vaccination of AdCLD-CoV19. Furthermore, the adenovirus-induced Th1 immune response was specifically raised for the S protein, and these immune responses protected the NHP against live viruses. While AdCLD-CoV19 maintained neutralizing antibody activity against various SARS-CoV-2 variants, it was reduced to single vaccination for ß and ο variants, and the reduced neutralizing antibody activity was restored with booster shots. Hence, AdCLD-CoV19 can prevent SARS-CoV-2 with a single vaccination, and the new vaccine administration strategy that responds to various variants can maintain the efficacy of the vaccine.

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