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BACKGROUND: The incidence of non-suicidal self-injury (NSSI) has been on the rise in recent years. Studies have shown that people with NSSI have difficulties in emotion regulation and cognitive control. In addition, some studies have investigated the cognitive emotion regulation of people with NSSI which found that they have difficulties in cognitive emotion regulation, but there was a lack of research on cognitive emotion regulation strategies and related neural mechanisms. METHODS: This study included 117 people with NSSI (age = 19.47 ± 5.13, male = 17) and 84 non-NSSI participants (age = 19.86 ± 4.14, male = 16). People with NSSI met the DSM-5 diagnostic criteria, and non-NSSI participants had no mental or physical disorders. The study collected all participants' data of Cognitive Emotion Regulation Questionnaire (CERQ) and functional magnetic resonance imaging (fMRI) to explore the differences in psychological performance and brain between two groups. Afterwards, Machine learning was used to select the found differential brain regions to obtain the highest correlation regions with NSSI. Then, Allen's Human Brain Atlas database was used to compare with the information on the abnormal brain regions of people with NSSI to find the genetic information related to NSSI. In addition, gene enrichment analysis was carried out to find the related pathways and specific cells that may have differences. RESULTS: The differences between NSSI participants and non-NSSI participants were as follows: positive refocusing (t = -4.74, p < 0.01); refocusing on plans (t = -4.11, p < 0.01); positive reappraisal (t = -9.22, p < 0.01); self-blame (t = 6.30, p < 0.01); rumination (t = 3.64, p < 0.01); catastrophizing (t = 9.10, p < 0.01), and blaming others (t = 2.52, p < 0.01), the precentral gyrus (t = 6.04, pFDR < 0.05) and the rolandic operculum (t = -4.57, pFDR < 0.05). Rolandic operculum activity was negatively correlated with blaming others (r = -0.20, p < 0.05). Epigenetic results showed that excitatory neurons (p < 0.01) and inhibitory neurons (p < 0.01) were significant differences in two pathways, "trans-synaptic signaling" (p < -log108) and "modulation of chemical synaptic transmission" (p < -log108) in both cells. CONCLUSIONS: People with NSSI are more inclined to adopt non-adaptive cognitive emotion regulation strategies. Rolandic operculum is also abnormally active. Abnormal changes in the rolandic operculum of them are associated with non-adaptive cognitive emotion regulation strategies. Changes in the excitatory and inhibitory neurons provide hints to explore the abnormalities of the neurological mechanisms at the cellular level of them. Trial registration number NCT04094623.
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Regulación Emocional , Imagen por Resonancia Magnética , Conducta Autodestructiva , Humanos , Conducta Autodestructiva/psicología , Conducta Autodestructiva/fisiopatología , Masculino , Femenino , Regulación Emocional/fisiología , Adulto , Adulto Joven , Adolescente , Cognición/fisiología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encuestas y CuestionariosRESUMEN
BACKGROUND: we aimed to explore the relationship of acute kidney injury (AKI) with the severity and mortality of coronavirus disease 2019 (COVID-19). METHODS: A systematic literature search was conducted in PubMed, EMBASE, Scopus, Web of Science, MedRxiv Database. We compared the laboratory indicators of renal impairment and incidences of AKI in the severe versus non-severe cases, and survival versus non-survival cases, respectively. RESULTS: In 41 studies with 10,335 COVID-19 patients, the serum creatinine (sCr) in severe cases was much higher than that in non-severe cases (SMD = 0.34, 95% CI: 0.29-0.39), with a similar trend for blood urea nitrogen (BUN) (SMD = 0.66, 95%CI: 0.51-0.81), hematuria (OR = 1.59, 95% CI: 1.15-2.19), and proteinuria (OR = 2.92, 95% CI: 1.58-5.38). The estimated glomerular filtration rate decreased significantly in severe cases compared with non-severe cases (SMD = -0.45, 95% CI: -0.67- -0.23). Moreover, the pooled OR of continuous renal replacement therapy (CRRT) and AKI prevalence for severe vs. non-severe cases was 12.99 (95%CI: 4.03-41.89) and 13.16 (95%CI: 10.16-17.05), respectively. Additionally, 11 studies with 3759 COVID-19 patients were included for analysis of disease mortality. The results showed the levels of sCr and BUN in non-survival cases remarkably elevated compared with survival patients, respectively (SMD = 0.97, SMD = 1.49). The pooled OR of CRRT and AKI prevalence for non-survival vs. survival cases was 31.51 (95%CI: 6.55-151.59) and 77.48 (95%CI: 24.52-244.85), respectively. CONCLUSIONS: AKI is closely related with severity and mortality of COVID-19, which gives awareness for doctors to pay more attention for risk screening, early identification and timely treatment of AKI.
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Lesión Renal Aguda/etiología , COVID-19/epidemiología , Lesión Renal Aguda/epidemiología , COVID-19/complicaciones , Salud Global , Humanos , Incidencia , Prevalencia , Factores de Riesgo , SARS-CoV-2 , Tasa de Supervivencia/tendenciasRESUMEN
The immunogenicity of COVID-19 vaccines in patients with liver cirrhosis remains largely unknown. The purpose of this meta-analysis was to investigate the immunogenicity of COVID-19 vaccines in patients with cirrhosis and compare the humoral and cellular immune responses following complete COVID-19 vaccination between cirrhosis patients and healthy controls. A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from 1 January 2020 to 22 August 2023. Sixteen studies with 2127 cirrhosis patients were included. The pooled seroconversion rate in patients with cirrhosis following complete COVID-19 vaccination was 92.4% (95% CI, 86.2%-96%, I2 = 90%) with significant between-study heterogeneity. Moreover, COVID-19 vaccination elicited a higher humoral immune response in patients of compensated cirrhosis as compared with decompensated cirrhosis (RR = 1.069, 95% CI, 1.011-1.131, I2 = 17%, p = .019). Additionally, 10 studies were included for comparison analysis of seroconversion rate between cirrhosis patients and healthy controls. The results showed that the seroconversion rate in patients with cirrhosis was slightly lower compared with healthy controls (RR = 0.972, 95% CI, 0.955-0.989, I2 = 66%, p = .001). Meanwhile, the pooled RR of cellular immune response rate for cirrhosis patients vs. healthy controls was 0.678 (95% CI, 0.563-0.817, I2 = 0, p < .0001). Our meta-analysis demonstrated that COVID-19 vaccination elicited diminished humoral and cellular immune responses in patients of cirrhosis. Patients with cirrhosis particularly decompensated cirrhosis who have completed full-doses of COVID-19 vaccination should receive continuous attention and preemptive measures.
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Vacunas contra la COVID-19 , COVID-19 , Inmunogenicidad Vacunal , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunidad Humoral , Cirrosis Hepática/complicaciones , PacientesRESUMEN
Raising tumor-specific allorestricted T cells in vitro for adoptive transfusion is expected to circumvent host tumor tolerance. However, it has been assumed that alloreactive T cell clones activated in vitro ranges from peptide-specific with high avidity to peptide-degenerate with low avidity. In this study, we examined the peptide specificity and cross-reactivity of T cell responses in vitro to an allogeneic epitope and a nominal epitope with a modified co-culture of lymphocytes and autologous monocytes. After binding to the monocyte via the interaction of its Fc part and the cell surface IgG Fc receptor type I (FcγRI), a fusion protein consisting of the extracellular domains of HLA-A2 molecule and the Fc region of IgG1 (the dimer) introduced a single epitope into the co-culture. The dimer-coated monocytes stimulated the proliferation of autologous CD8(+) T cells after co-culturing. The CD8(+) T cell responses were self-HLA-restricted for HLA-A2-positive (HLA-A2+ve) samples and allo-HLA-restricted for HLA-A2-negative (HLA-A2-ve) samples, since the co-cultural bulks stained with HLA-A2 tetramers, human interferon-gamma (IFN-γ) production in response to T cell receptor (TCR) ligands, and cytotoxicity against a panel of target cells exhibited peptide-specific properties. Two HLA-A2-restricted peptides with sequence homology were included, allowing the comparison of cross-reactivity between allo-antigen- and nominal antigen-induced CD8(+) T cell responses. Interestingly, the allo- and self-HLA-restricted CD8(+) T cell responses were similar in the peptide cross-reactivity, although the allorestricted T cell response seemed, overall, more intensive and had higher binding affinity to specific tetramer. Our findings indicated the alloreactive T cells raised by the co-culture in vitro were as peptide specific and cross-reactive as the self-HLA-restricted ones.
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Linfocitos T CD8-positivos/inmunología , Isoantígenos/inmunología , Fragmentos de Péptidos/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Antígenos de Neoplasias/inmunología , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Dimerización , Antígenos VIH/inmunología , Antígeno HLA-A2/inmunología , Antígenos de la Hepatitis C/inmunología , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Ensayos de Liberación de Interferón gamma , Activación de Linfocitos , Monocitos/inmunología , Monofenol Monooxigenasa/inmunología , Proteínas no Estructurales Virales/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
Antisocial personality disorder (ASPD) is a common behavioral pattern that causes sufferers to ignore or violate the rights of others. Though its cause is still unclear, previous studies have shown that childhood maltreatment is closely related to ASPD. The NOS1AP gene is associated with various neuropsychiatric diseases, but a linkage between it and ASPD has not yet been discovered. This study recruited ASPD and non-ASPD male subjects who had committed violent crimes from a prison in Nanjing, China. By comparing the two groups' genotypes, allele frequencies, and histories of childhood abuse, we explored the interaction between the NOS1AP gene and childhood maltreatment on the pathogenesis of ASPD. The results showed that polymorphism rs945713 in the NOS1AP gene was associated with ASPD and furthermore that this SNP may be involved in regulating the effect of childhood abuse on ASPD. This study found that childhood trauma increases the risk of ASPD in violent adult male inmates; for prisoners with ASPD, it is critical to pay attention to their childhood trauma and take early psychological intervention.
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Trastorno de Personalidad Antisocial , Maltrato a los Niños , Adulto , Humanos , Masculino , Niño , Trastorno de Personalidad Antisocial/genética , Trastorno de Personalidad Antisocial/psicología , Pueblos del Este de Asia , Polimorfismo Genético , Violencia/psicología , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Non-small cell lung cancer (NSCLC) is one of the important causes of cancer-related mortality worldwide. Previous studies have demonstrated the crucial roles of mucosal-associated invariant T (MAIT) cells in regulating tumor immunity, while their roles in NSCLC remain largely unknown. The aim of this study is to evaluate clinical relevance of MAIT cells in blood and tumor tissues of patients with NSCLC. Here, we find that there is no significant difference in the frequency of circulating MAIT cells between NSCLC patients and healthy donors. However, the MAIT-frequency is significantly declined in lung tumor tissues compared to their peri-tumor counterparts, which relates to Tumor-Node-Metastasis (TNM) stage. The MAIT-frequency in lung tumor tissues is higher in node-negative patients compared to node-positive patients. Furthermore, tumor-infiltrating MAIT cells display a tissue-resident effector-memory phenotype and exhibit upregulated levels of exhaustion markers. The percentage of tissue-resident cells in MAIT tends to be higher in tumor tissues than in peri-tumor tissues. In addition, the percentage of IL-17A+ MAIT cells is significantly higher in lung tumor tissues than that in peri-tumor tissues. In summary, our results indicate the possible detrimental role of MAIT cells in the development and progression of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Células T Invariantes Asociadas a Mucosa , Humanos , Interleucina-17 , FenotipoRESUMEN
INTRODUCTION: We aimed to describe the respiratory supports and determine their association with clinical outcomes of COVID-19 patients in intensive care unit (ICU). METHODS: A systemic literature search was conducted in PubMed, EMBASE, MedRxiv and BioRxiv database from December 2019 to 2 July 2020. Studies reporting the application of respiratory supports in COVID-19 patients admitted to ICU were included. RESULTS: Forty studies with 15320 COVID-19 patients were included in this systematic review. The proportion of invasive mechanical ventilation (IMV) application in ICU patients with COVID-19 was 73.8%. Further analysis elucidated that the use rate of IMV in Asia, Europe and North America was 47%, 76.2% and 80.2%, respectively. The proportion of patients treated with prone positioning and IMV was 29.4%. 25.5% of COVID-19 patients requiring IMV developed ventilator-associated pneumonia. The mortality of patients treated with IMV was 51.1%, while only 17.5% of critically ill COVID-19 patients treated with non-IMV respiratory support died. Additionally, the utilization rate of IMV in non-survival patients was shown 17.26-folds (95%CI 2.89-103.24, p = 0.002) higher than that in survival patients, while the use rate of ECMO was no significant difference. CONCLUSIONS: Our findings highlight respiratory supports of COVID-19 patients admitted to ICU in different continents. IMV is a life-saving strategy for critically ill COVID-19 patients with ARDS, yet the mortality remains very high.
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BACKGROUND: The impact of pre-existing interstitial lung disease (ILD) on the severity and mortality of COVID-19 remains largely unknown. The purpose of this meta-analysis was to investigate the prevalence of ILD among patients with COVID-19 and figure out the relationship between ILD and the poor clinical outcomes of COVID-19. METHODS: A systematic literature search was conducted in the PubMed, EMBASE, Web of Science and MedRxiv Database from 1 January 2020 to 26 May 2021. RESULTS: 15 studies with 135,263 COVID-19 patients were included for analysis of ILD prevalence. The pooled prevalence of comorbid ILD in patients with COVID-19 was 1.4% (95% CI, 1.1%-1.8%, I2 = 91%) with significant between-study heterogeneity. Moreover, the prevalence of ILD in non-survival patients with COVID-19 was 2.728-folds higher than that in corresponding survival patients (RR = 2.728, 95% CI 1.162-6.408, I2 = 54%, p = 0.021). Additionally, 2-3 studies were included for comparison analysis of clinical outcome between COVID-19 patients with and without ILD. The results showed that the mortality of COVID-19 patients with ILD was remarkably elevated compared with patients without ILD (RR = 2.454, 95% CI 1.111-5.421, I2 = 87%, p = 0.026). Meanwhile, the pooled RR of ICU admission for ILD vs. non-ILD cases with COVID-19 was 3.064 (95% CI 1.889-4.972, I2 = 0, p < 0.0001). No significant difference in utilizing rate of mechanical ventilation was observed between COVID-19 patients with and without ILD. CONCLUSIONS: There is great variability in ILD prevalence among patients with COVID-19 across the globe. Pre-existing ILD is associated with higher severity and mortality of COVID-19.
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COVID-19/mortalidad , Enfermedades Pulmonares Intersticiales/epidemiología , SARS-CoV-2 , Humanos , Unidades de Cuidados Intensivos , Enfermedades Pulmonares Intersticiales/complicaciones , Prevalencia , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The recent application of blended educational methods has impacted medical education and has drawn attention to a new teaching method. This teaching style presents unique opportunities and challenges. We investigated the effects of blended learning and traditional teaching methods on clinical skill development. METHODS: We sorted 200 medical students from Tongji Medical College at Huazhong University of Science and Technology into a control or experimental group. The control group was taught with a traditional lecture-based learning method and the experimental group was taught using a blended learning method. The two groups were compared after training to assess their theoretical and practical differences. A student satisfaction survey was given to participants in both groups. RESULTS: The results of the experimental group's theoretical and practical assessments were found to be significantly higher (p < 0.05) than that of the control group. The student satisfaction survey showed that blended learning was significantly more effective for acquiring relevant knowledge, enhancing student-centered learning and improving clinical practice. CONCLUSIONS: Blended learning may address deficiencies in clinical skills, make up for limited time and space, and ensure learning efficiency and quality.
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Community-acquired pneumonia (CAP) remains the significant infectious cause of morbidity and mortality worldwide. Although mucosal-associated invariant T cells (MAIT) play roles in the pathogenesis of children CAP and ICU-associated pneumonia, their roles in adult CAP are largely unexplored. In this study, we investigated the frequency, phenotype, and function of MAIT cells in peripheral blood and bronchoalveolar lavage fluid (BALF) of adult CAP patients. Our data indicate that MAIT-cell frequency is profoundly lower in the peripheral blood of CAP patients compared to that in healthy individuals. Furthermore, the circulatory MAIT cells express higher levels of CD69 and PD-1 compared to those in healthy individuals. In BALF of CAP patients, MAIT-cell frequency is higher and MAIT cells express higher levels of CD69 and PD-1 compared to their matched blood counterparts. Levels of IL-17A and IFN-γ are increased in BALF of CAP patients compared to those in BALF of patients with pulmonary small nodules. The IL-17A/IFN-γ ratio is significantly positively correlated with MAIT frequency in BALF of CAP patients, suggesting a pathogenic role of MAIT-17 cells in CAP. Of note, blood MAIT-cell frequency in CAP patients is strongly negatively correlated with high-sensitivity C-reactive protein (hsCRP) and neutrophil count percentage in blood. The ability of circulating MAIT cells in CAP patients to produce IFN-γ is significantly impaired compared to those in healthy individuals. In summary, our findings suggest the possible involvement of MAIT cells in the immunopathogenesis of adult CAP.
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Infecciones Comunitarias Adquiridas/inmunología , Activación de Linfocitos , Células T Invariantes Asociadas a Mucosa/inmunología , Neumonía/inmunología , Adulto , Anciano , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Broncoscopía , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/patología , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/metabolismo , Neumonía/sangre , Neumonía/diagnóstico , Neumonía/patologíaRESUMEN
Immune dysregulation characterized by T cell exhaustion and high level of inflammatory cytokines is associated with severe COVID-19. Figuring out the early event of immune dysregulation would provide a potential treatment for COVID-19. Recent evidence indicate that mitochondrial dysfunction participates in the development of COVID-19 and may be responsible for the dysregulated immune response. Mitochondrial-targeted ubiquinone (MitoQ), a mitochondrial-targeted antioxidant, shows beneficial effects on various diseases through improving mitochondrial dysfunction. We hypothesize that MitoQ could act as a potential treatment in COVID-19. MitoQ may alleviate cytokine storm and restore the function of exhausted T cells in COVID-19 patients through improving mitochondrial dysfunction. In this article, we provide evidence to support the use of MitoQ as a potential treatment or adjunct therapy in the context of COVID-19.
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Tratamiento Farmacológico de COVID-19 , Mitocondrias/efectos de los fármacos , Compuestos Organofosforados/uso terapéutico , Ubiquinona/análogos & derivados , Citocinas/metabolismo , Humanos , Sistema Inmunológico , Modelos Teóricos , Especies Reactivas de Oxígeno/metabolismo , Resultado del Tratamiento , Ubiquinona/uso terapéuticoRESUMEN
In this study, we aimed to investigate the effect of electro-acupuncture (EA) at the Zusanli acupoint (ST36) on interleukin (IL)-33-mediated mast cell activation. Firstly, 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in rats was developed with or without EA treatment. Then, rat peritoneal mast cells (RPMCs) were obtained and cultured in the presence of IL-33. EA treatment relieved ear swelling and reduced mast cell infiltration in the local inflammation area with DNFB challenge, accompanying the decrement of IL-33 production. RPMCs isolated from ACD rats with EA treatment showed significant downregulation of IL-6, TNF-α, IL-13, and MCP-1 production following IL-33 stimulation. However, there was no obvious difference in surface ST2 receptor expression among different groups. In addition, EA selectively altered IL-33 signaling, suppressing p38 phosphorylation as well as NF-κB- and AP-1-mediated transcription but not Akt phosphorylation. Importantly, EA lowered microRNA (miR)-155 expression in the RPMCs, which presented a positive correlation with IL-33-induced IL-6 production. Furthermore, overexpression of miR-155 in the RPMCs was established following miR-155 mimic transfection. RPMCs with the overexpressed miR-155 displayed an obvious increment of inflammatory cytokine and abrogated the inhibitive effect of EA on NF-κB- and AP-1-regulated transcription in response to IL-33 compared with those without transfected-miR-155. These findings demonstrate EA treatment inhibits NF-κB and AP-1 activation as well as promotes the negative feedback regulation of IL-33 signaling via targeting miR-155 in mast cells, which contribute to the anti-inflammatory effect of EA on DNFB-induced ACD in rats.
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Dermatitis Alérgica por Contacto/terapia , Electroacupuntura , Inflamación/tratamiento farmacológico , Interleucina-33/metabolismo , MicroARNs/efectos de los fármacos , Transducción de Señal , Animales , Retroalimentación Fisiológica , Mastocitos/patología , RatasRESUMEN
CD8(+) suppressor T cells have been demonstrated to provide protection of allografts from rejection. We previously reported that soluble peptide/HLA-A2 dimer shows peptide-specific inhibitory effects on alloresponse in a coculture of peptide-pulsed T2 cells with HLA-A2 negative lymphocytes in vitro. Here we found a subset of CD8(low)CD28(-) T cells that was induced in the dimer-treated coculture. Importantly, this population showed hyporesponsiveness to the alloantigen restimulation as well as alloantigen-specific suppression on alloreactive T cells in a cell-cell contact-dependent fashion. The suppressive mechanisms of CD8(low)CD28(-) T cells involved an elevated expression of membrane-bound TGF-ß1, but not Foxp3, CTLA-4, or IL-10. Furthermore, an overrepresention of CD8(low)CD28(-) T cells was observed in the patients after allogeneic platelet transfusion and positively correlated with the elevated concentrations of plasma HLA class I antigens. Our findings demonstrated that soluble HLA-A2 dimer could efficiently induce the tolerant CD8(low)CD28(-) T cells with alloantigen-specific suppression on alloreactive T cells. This study might provide a new strategy for preparation of donor-specific suppressor T cells and represent an attractive alternative for induction of allograft tolerance.
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Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno HLA-A2/inmunología , Isoantígenos/inmunología , Activación de Linfocitos/inmunología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/inmunología , Trasplante Homólogo/métodosRESUMEN
Recent studies suggest that CD8(+) T cells with down-regulated CD8 expression (CD3(+)CD8(low) T cells) represented as a distinct phenotype of CD8(+) T cells are increased and linked to disease severity in some chronically persistent infection, such as chronic HIV and parasite infection. However, the role of CD3(+)CD8(low) T cells in the context of chronic HBV infection is poorly understood. In this study, peripheral blood samples of 47 chronic hepatitis B patients and 19 healthy controls were collected and tested for the frequency and phenotype of CD8(low) T cells. The circulating CD8(low) T cells were significantly more frequent in the patients compared to those in healthy controls, and the CD8(low) T cells in the patients expressed less IFN-γ and more mTGF-ß1 than those in the controls, suggesting their type-2 polarized and suppressive properties. Meanwhile, the concentrations of plasma soluble HLA class I molecules were found elevated in the patients, and positively associated with the frequencies of CD8(low) T cells. Furthermore, the CD8(low) T-cell frequency in the HLA-A2-positive patients (n=21) was found negatively correlated with the T-cell responsiveness against the HBc18â27 peptide, the latter was impaired as revealed by IFN-γ Elispot assay. Our findings suggested that a better understanding of the involvement of CD8(low) T cells in chronically persistent HBV infection would add to our knowledge of the impaired T-cell response in the patients.
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Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Adulto , Anciano , Complejo CD3/inmunología , Complejo CD3/metabolismo , Antígenos CD8/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta1/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Adulto JovenRESUMEN
The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-A(b) fusion protein (MOG35-55/I-A(b) dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-A(b) dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-ß (mTGF-ß) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.
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Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Epítopos de Linfocito T/inmunología , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Linfocitos T/patología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Generation of tumor specific alloreactive CD4(+) T cells is important to circumvent tumor tolerance. Here, we generate allorestricted peptide-specific CD4(+) T cells by coculture of lymphocytes and autologous monocytes bearing allogeneic HLA-DR15 molecule associated with its restricted peptide. Binding of a dimeric HLA-DR15/IgG1-Fc fusion protein (the dimer) to HLA-DR15 negative (HLA-DR15-ve) monocytes made the monocytes coated with the allogeneic epitope. An increased proliferation of CD4(+) T cells and induction of Th1 cells appeared after coculturing of HLA-DR15-ve lymphocytes and the autologous monocytes loaded with the dimer. The cocultural bulks showed an increased frequency of the specific dimer-stained CD4(+) T cells and the expanded CD4(+) T cells exhibited an elevated IFN-γ production in response to specific TCR ligand. Tumor rejection effects of the allorestricted E7-specific CD4(+) T cells raised by the coculture were observed in nude mice challenged with human cervical cancer cell SiHa expressing both HLA-DR15 and E7 antigens, as the tumor avoidance and life span of the mice were improved after adoptive transfer of the CD4(+) T cells. This study may help to develop strategies to separate graft-versus-leukemia or graft-versus-tumor reaction from graft-versus-host disease, and add to the pool of human high-avidity TCRs specific for tumor or virus antigens.