Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.845
Filtrar
1.
Lab Invest ; 100(6): 794-800, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341519

RESUMO

Timely analysis of the laboratory characteristics associated with 2019 novel coronavirus pneumonia (COVID-19) can assist with clinical diagnosis and prognosis. This study is a collection of clinical data from 54 hospitalized adult patients diagnosed with COVID-19 in the Zhongfa Xincheng district of China at Tongji Hospital of Huazhong University of Science and Technology from January 28, 2020 to February 11, 2020. The average age of the patients was 61.8 ± 14.5 years, and the predominant age group was 50-79. The proportion of critical-type patients with comorbidities was higher than that of severe-type patients. Lymphocyte counts were significantly reduced in routine bloodwork for all patients, but significantly lower in critical-type patients than that in severe-type patients. Prolongation of prothrombin times (PT) and elevation of fibrinogen degradation products (FDPs) and D-dimers (D-Ds) were detected in coagulation function tests, and more significant changes were observed in critical-type patients compared to severe-type patients. Serum ferritin levels were sensitive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but could not be used for disease assessment. In addition, levels of two inflammatory factors, soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) were significantly increased in all patients, but higher in critical-type patients than in severe-type patients. Moreover, kidney injury was the second-most common organ affected by COVID-19 followed by heart and liver. Kidney and heart injury were more severe in critical-type patients than in severe-type patients. All of the 31 severe-type patients recovered. Of the critical-type patients, six died and 17 recovered. The length of hospital stay for critical-type patients was significantly longer for severe-type patients. In summary, increased lymphocyte counts, prolonged PT, secondary increases in fibrinolytic activity and increases in sIL-2R and IL-6 are typical features of COVID-19 and are associated with disease severity.


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Comorbidade , Infecções por Coronavirus/diagnóstico , Feminino , Ferritinas/sangue , Fibrinólise , Cardiopatias/virologia , Humanos , Interleucina-6/sangue , Nefropatias/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Receptores de Interleucina-2/sangue , Estudos Retrospectivos , Adulto Jovem
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(3): 203-208, 2020 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-32164089

RESUMO

Objective: To analyze the clinical characteristics of 2019 novel coronavirus (2019-nCoV) pneumonia and to investigate the correlation between serum inflammatory cytokines and severity of the disease. Methods: 29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology in January 2020 were selected as the study subjects. Clinical data were collected and the general information, clinical symptoms, blood test and CT imaging characteristics were analyzed. According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease. Results: (1) The main symptoms of 2019-nCoV pneumonia was fever (28/29) with or without respiratory and other systemic symptoms. Two patients died with underlying disease and co-bacterial infection, respectively. (2) The blood test of the patients showed normal or decreased white blood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (27/29), and normal procalcitonin. In most patients, serum lactate dehydrogenase (LDH) was significantly increased (20/29), while albumin was decreased (15/29). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil), serum creatinine (Scr) and other items showed no significant changes. (3) CT findings of typical cases were single or multiple patchy ground glass shadows accompanied by septal thickening. When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow. (4) There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (P<0.05), among which the critical group was higher than the severe group and the severe group was higher than the mild group. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05). Conclusion: The clinical characteristics of 2019-nCoV pneumonia are similar to those of common viral pneumonia. High resolution CT is of great value in the differential diagnosis of this disease. The increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the 2019-nCoV pneumonia and the prognosis of patients.


Assuntos
Betacoronavirus/isolamento & purificação , Biomarcadores , Infecções por Coronavirus/diagnóstico , Interleucina-6/metabolismo , Pneumonia Viral/diagnóstico , Receptores de Interleucina-2/metabolismo , Biomarcadores/sangue , Infecções por Coronavirus/metabolismo , Citocinas/sangue , Humanos , Pulmão/diagnóstico por imagem , Pneumonia Viral/metabolismo , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
3.
Nat Commun ; 11(1): 660, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005809

RESUMO

Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor ßγ (IL-2Rßγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rßγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.


Assuntos
Transferência Adotiva , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Animais , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/imunologia , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética
4.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
PLoS One ; 14(10): e0223897, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622413

RESUMO

BACKGROUND: The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases. METHODS: A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden's Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis. RESULTS: In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p<0.0001). CONCLUSION: Serum sIL-2R is a sensitive biomarker and superior to ACE in establishing the diagnosis of sarcoidosis and can be used to rule out sarcoidosis in patients suspected of sarcoidosis.


Assuntos
Biomarcadores/sangue , Receptores de Interleucina-2/sangue , Sarcoidose/diagnóstico , Adulto , Estudos de Coortes , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/sangue , Curva ROC , Sarcoidose/metabolismo , Sensibilidade e Especificidade
6.
Anticancer Res ; 39(9): 5115-5122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519623

RESUMO

BACKGROUND/AIM: Although various prognostic indices for follicular lymphoma (FL) have been proposed, they are designed specifically for patients requiring immediate therapy. We aimed to develop a new simple prognostic tool applicable for all patients with FL at diagnosis. MATERIALS AND METHODS: We retrospectively analyzed various clinical, pathological, and laboratory data, including soluble interleukin-2 receptor (sIL2R), from 140 patients with FL from two centers for their impact on prognosis. This study analyzed the impact of soluble interleukin-2 receptor (sIL2R) in order to develop a new simple prognostic tool applicable for all patients with FL at diagnosis. RESULTS: The initial management of these patients was watchful waiting (n=48) or immediate treatment (n=92). Event-free survival at 24 months predicted overall survival. When categorized into three groups according to the sIL2R levels at diagnosis, a very high sIL2R level identified about 20% of patients with a distinctively worse survival compared to the others. CONCLUSION: sIL2R is a very effective biomarker that can be easily applied in routine practice to predict survival for all patients with FL at diagnosis irrespective of initial management approach.


Assuntos
Biomarcadores Tumorais , Linfoma Folicular/sangue , Linfoma Folicular/mortalidade , Receptores de Interleucina-2/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Gerenciamento Clínico , Feminino , Humanos , Linfoma Folicular/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
7.
Tohoku J Exp Med ; 248(3): 209-216, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31366819

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Pneumocystis carinii/fisiologia , Pneumonia/sangue , Pneumonia/complicações , Receptores de Interleucina-2/sangue , Idoso , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Pneumonia/microbiologia , Curva ROC , Solubilidade , Tomografia Computadorizada por Raios X
8.
Ann Hematol ; 98(9): 2121-2129, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240469

RESUMO

We retrospectively analyzed 70 patients with classical Hodgkin lymphoma (cHL) who were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiotherapy to assess the influence of the soluble interleukin-2 receptor (sIL-2R) level at diagnosis on the clinical outcome. Receiver operating characteristic analyses determined that the optimal cutoff value of the sIL-2R level for progression-free survival (PFS) was 2490 U/mL. Using this cutoff value, patients were classified into low (n = 46) and high (n = 24) sIL-2R groups. The patients in the high sIL-2R group exhibited a significantly inferior PFS (44.1% vs. 90.4% at 5 years, P < 0.001) and overall survival (OS) (67.6% vs. 94.7% at 5 years, P = 0.001) compared with those in the low sIL-2R group. Multivariate analysis showed that a high sIL-2R level was an independent prognostic factor for PFS after adjusting for stage, white blood cell, hemoglobin, and B symptoms, and also OS after adjusting for age and stage (hazard ratio (HR) 6.49, P < 0.001 and HR 5.98, P = 0.009, respectively). In patients with advanced-stage cHL, a high sIL-2R level predicted 5-year PFS even after adjustment for international prognostic score > 4 (HR 6.00, P = 0.007). These results demonstrate that the sIL-2R level can be a useful prognostic factor in patients with cHL treated with ABVD with or without radiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia , Doença de Hodgkin , Proteínas de Neoplasias/sangue , Receptores de Interleucina-2/sangue , Adolescente , Adulto , Idoso , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/sangue , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Vimblastina/administração & dosagem
9.
Int J Clin Oncol ; 24(9): 1151-1160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31183777

RESUMO

BACKGROUND: Patients on chronic hemodialysis (HD) have an increased incidence of malignancy due to decreased immunity. Soluble interleukin-2 receptor (sIL-2R), as an immunomodulator, seemed to have an effect in the process of malignancy. In this study, we aimed to evaluate the clinical significance of increased sIL-2R in the course of malignancy among HD patients. METHODS: Patients who undergoing chronic hemodialysis were followed for 24 months. Risk factors for malignancy events and malignancy-related mortality during the 2-year follow-up period were investigated among various clinicopathological variables. RESULTS: Of the 363 patients included in this research, 47 patients (12.95%) had a prior history of treated malignancy. During the 2-year follow-up period, malignancy events were detected in 15 (4.12%) patients. Sixty-seven patients died during the study period, of which nine patients (13.43%) were died of malignancy. Malignancy events reduced 2-year mortality significantly (log-rank = 23.02, P < 0.0001). Both high sIL-2R levels ( ≥ 2-fold upper limit of the normal value) (OR 6.6, P = 0.006) and a prior history of treated malignancy (OR 4.12, P = 0.018)were identified by multivariate logistic analysis as independent determinants for malignancy events. However, only the levels of sIL-2R (used as a continuous variable) had the significantly predictive effect on malignancy events and malignancy-related mortality in the following 2 years. CONCLUSIONS: Elevated sIL-2R levels was commonly seen in serum of HD patients. And this elevated level increased the risk of malignancy. Aside from its role as a biomarker, sIL-2R may also exert biological effects in the course of malignancy.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias/sangue , Receptores de Interleucina-2/sangue , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia
10.
Cell Immunol ; 340: 103916, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31126634

RESUMO

Itch is a HECT type E3 ubiquitin ligase that is required to prevent the development of autoimmune disease in both mice and humans. Itch is expressed in most mammalian cell types, and, based on published data, it regulates many cellular pathways ranging from T cell differentiation to liver tumorigenesis. Since 1998, when Itch was first discovered, hundreds of publications have described mechanisms through which Itch controls various biologic activities in both immune and non-immune cells. Other studies have provided insight into how Itch catalytic activity is regulated. However, while autoimmunity is the primary clinical feature that occurs in both mice and humans lacking Itch, and Itch control of immune cell function has been well-studied, it remains unclear how Itch prevents the emergence of autoimmune disease. In this review, we explore recent discoveries that advance our understanding of how Itch regulates immune cell biology, and the extent to which these clarify how Itch prevents autoimmune disease. Additionally, we discuss how molecular regulators of Itch impact its ability to control these processes, as this may provide clues on how to therapeutically target Itch to treat patients with autoimmune disease.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Neoplasias Hepáticas/imunologia , Proteínas Repressoras/genética , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/genética , Animais , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Linfócitos B/enzimologia , Linfócitos B/patologia , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Interleucina-2/genética , Interleucina-2/imunologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/imunologia , Transdução de Sinais , Linfócitos T/enzimologia , Linfócitos T/patologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/imunologia
11.
J Dermatol ; 46(7): 577-583, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31131913

RESUMO

Sarcoidosis and systemic sclerosis (SSc) are both multisystem disorders of unknown etiology. Some cases having both sarcoidosis and SSc have been reported previously. The present study was to investigate clinical features in sarcoidosis patients who possessed SSc-specific autoantibody. The pathophysiology of each disease, including shared pathways leading to the development of both conditions, is reviewed in addition to previous reports of patients with concomitant SSc and sarcoidosis. SSc-specific autoantibodies including anticentromere antibody (ACA), anti-topoisomerase I antibody, anti-RNA polymerase III antibody and anti-U1RNP antibody were examined in sarcoidosis patients. Complete medical histories, clinical examinations and laboratory tests were conducted for all patients. For reviewing previously published reports, all cases were retrieved through a PubMed search. ACA was most frequently observed in sarcoidosis patients. Plaques and papules were the most frequent as the cutaneous sarcoidosis lesions. Soluble interleukin-2 receptor was elevated in most of the cases (6/8, 75%), and thymus and activation-regulated chemokine (TARC) was elevated in all cases (6/6, 100%). Together with our two cases (cases 1 and 3), a review of previously reported cases of sarcoidosis patients concomitant with SSc showed high frequency of ACA and plaques as cutaneous lesions. We suppose that TARC may play some roles in the production of SSc-specific autoantibodies and development of concomitance with SSc in sarcoidosis, although the mechanisms remain unknown.


Assuntos
Autoanticorpos/sangue , Quimiocina CCL17/imunologia , Sarcoidose/imunologia , Escleroderma Sistêmico/imunologia , Autoanticorpos/imunologia , Quimiocina CCL17/metabolismo , Humanos , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Sarcoidose/sangue , Sarcoidose/patologia , Escleroderma Sistêmico/sangue , Pele/imunologia , Pele/patologia
13.
Rinsho Ketsueki ; 60(3): 203-208, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068516

RESUMO

An 81-year-old woman with type 2 diabetes mellitus presented to our hospital due to anorexia, leg edema, and respiratory distress. Laboratory results revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and markedly elevated soluble interleukin-2 receptor levels. Computed tomography showed ground-glass opacities and consolidation in both lung fields, but no lymphadenopathy was noted. Intravascular large B-cell lymphoma (IVLBCL) was considered as a differential diagnosis; therefore, bone marrow and random skin biopsy were performed. Her respiratory condition deteriorated, with the occurrence of acute respiratory distress syndrome, disseminated intravascular coagulation, hemophagocytic syndrome, and further alveolar hemorrhage. Methylprednisolone pulse therapy was performed, but did not improve the patient's condition. On hospital day 6, the acid-fast bacterial smear of the sputum using the Gaffky scale was 2, and on the next day, tuberculosis DNA was detected in the polymerase chain reaction. In the bone marrow biopsy, multiple epithelioid cell granulomas were found; thus, the patient was diagnosed with miliary tuberculosis. Although anti-tuberculosis therapy was started immediately, she died on hospital day 22. The soluble interleukin-2 receptor level increased up to 19,400 U/ml. The differential diagnosis should be cautiously made because miliary tuberculosis can mimic IVLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Interleucina-2/sangue , Tuberculose Miliar/diagnóstico , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Síndrome do Desconforto Respiratório do Adulto/complicações
14.
J Immunol ; 203(1): 93-104, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085588

RESUMO

Low-dose IL-2 therapy is a direct approach to boost regulatory T cells (Tregs) and promote immune tolerance in autoimmune patients. However, the mechanisms responsible for selective response of Tregs to low-dose IL-2 is not fully understood. In this study we directly assessed the contribution of CD25 and protein phosphatase 2A (PP2A) in promoting IL-2R signaling in Tregs. IL-2-induced tyrosine phosphorylation of STAT5 (pSTAT5) was proportional to CD25 levels on human CD4+ T cells and YT human NK cell line, directly demonstrating that CD25 promotes IL-2R signaling. Overexpression of the PP2A catalytic subunit (PP2Ac) by lentiviral transduction in human Tregs increased the level of IL-2R subunits and promoted tyrosine phosphorylation of Jak3 and STAT5. Interestingly, increased expression of CD25 only partially accounted for this enhanced activation of pSTAT5, indicating that PP2A promotes IL-2R signaling through multiple mechanisms. Consistent with these findings, knockdown of PP2Ac in human Tregs and impaired PP2Ac activity in mouse Tregs significantly reduced IL-2-dependent STAT5 activation. In contrast, overexpression or knockdown of PP2Ac in human T effector cells did not affect IL-2-dependent pSTAT5 activation. Overexpression of PP2Ac in human Tregs also increased the expressions of proteins related to survival, activation, and immunosuppressive function, and upregulated several IL-2-regulated genes. Collectively, these findings suggest that CD25 and PP2A cooperatively enhance the responsiveness of Tregs to IL-2, which provide potential therapeutic targets for low-dose IL-2 therapy.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Matadoras Naturais/imunologia , Proteína Fosfatase 2/metabolismo , Receptores de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Tolerância Imunológica , Janus Quinase 3/metabolismo , Ativação Linfocitária , Camundongos , Fosforilação , Ligação Proteica , Proteína Fosfatase 2/genética , Receptores de Interleucina-2/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
16.
Nagoya J Med Sci ; 81(1): 1-18, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30962651

RESUMO

CD4+ regulatory T cells (Tregs) expressing the transcription factor forkhead box P3 (FoxP3) play an important role in self-tolerance and immune homeostasis. Tregs have evolved to protect the host from aberrant immune responses against self-components and collateral damages occurring in the process of defense against invading pathogens by softening immune responses. However, they turned to be a scourge in malignant tumors by not only allowing and promoting tumor growth but also suppressing effective antitumor actions, both inherent (host's immune surveillance) and extrinsic (anticancer therapy). An increase in the number of Tregs infiltrating into tumor sites and a concomitant decrease in the number of CD8+ cytotoxic T lymphocytes are associated with a poor prognosis for various types of cancers, marking Tregs as notorious meddlers with an effective antitumor response. Various cancer immunotherapy approaches are often dampened by meddling Tregs, making them one of the major targets in the treatment of cancer. The recent success of immune checkpoint inhibitors (ICIs) that target immune checkpoint molecules expressed by Tregs or effector T cells implies, that "meddling with meddlers" represents an effective strategy in cancer immunotherapy. However, clinical responses to ICIs are effective and durable only in some patients with cancer, whereas more than half of them do not show significant clinical improvement. This implies that a therapeutic approach based on the use of a single ICI, or targeting Tregs alone, is insufficient, highlighting the need for combinatorial approaches. With regard to antitumor immune stimulation, several approaches, such as vaccination with peptides (or the corresponding DNA) to stimulate antigen-presenting CD8+ T cells with tumor-specific neoantigens, cancer/testis antigens, or cancer stem cell antigens, that eventually boost effective cytotoxic antitumor responses are being tested. This review describes the immunosuppressive physiology of Tregs and their meddling with the host's antitumor immunity; current and prospective approaches to curb Tregs; and approaches to augment antitumor immunity.


Assuntos
Linfócitos T Reguladores/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Tolerância Imunológica/imunologia , Tolerância Imunológica/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Modelos Biológicos , Receptor A2A de Adenosina/metabolismo , Receptores CCR4/metabolismo , Receptores de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia
17.
Int Immunopharmacol ; 72: 322-329, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005777

RESUMO

Interleukin-2 (IL-2) is a multifunctional cytokine in immune regulation. It is essential for the differentiation, expansion and stability of CD25+Foxp3+ regulatory T (Treg) cells, which is an important factor in immune suppression and self-tolerance. Meanwhile, IL-2 also stimulate effector T (Teff) cells to promote immune responses. The opposite and diverse function of IL-2 impedes its application to boost Treg cell populations in autoimmune disease treatment. Thus, it became focus of the research to modulate IL-2 activities to enhance Treg cell functions selectively. Based on the characteristic properties of Treg cells such as constitutively expression of high affinity IL-2 receptors (IL-2Rs), multiple approaches, including IL-2/mAb complexes, IL-2 muteins and low-dose of IL-2 have emerged in recent years to selectively target Treg cells and treat autoimmunity. These therapeutic approaches have achieved favorable results in both clinical trials and experimental animal models, and provided engineering blueprints to develop novel strategies of IL-2 treatments for autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Humanos , Receptores de Interleucina-2/imunologia
18.
Protein J ; 38(5): 525-536, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31006082

RESUMO

The inflammatory cytokine, interleukin-2 (IL-2), is an important regulator of cellular functions. This relatively less studied member of the interleukin protein family is responsible for multiple immuno-modulatory and immuno-stimulatory tasks, like T cell activation, triggering of natural killer cells, inflammation, as well as proliferation and progression of autoimmune diseases and cancers. In this communication we report the temporally variant structural aspects of the IL-2 ligand and its receptor interfaces, based on the available crystal structures. The intended goal of this effort is to generate simulated results that could potentially aid the designs of novel structure based therapeutics.


Assuntos
Interleucina-2/química , Biologia Computacional , Cristalografia por Raios X , Humanos , Inflamação/metabolismo , Interleucina-2/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Conformação Proteica , Mapas de Interação de Proteínas , Receptores de Interleucina-2/química , Receptores de Interleucina-2/metabolismo , Transdução de Sinais
19.
BMC Nephrol ; 20(1): 101, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902050

RESUMO

BACKGROUND: Recipients of living donor renal transplantation are typically considered to have a relatively lower immunological risk. This retrospective study aimed to compare the therapeutic efficacy and safety between rabbit antithymocyte globulin (rATG) or interleukin-2 receptor antagonist (IL2-RA) induction therapies in Chinese population. METHODS: A total of 188 patients receiving living donor renal transplantation between February 2004 and December 2013 were included and divided into the rATG group and based on their induction therapy. The primary outcome was clinically-suspected rejection. The incidences of de novo donor-specific antigen (dn-DSA), graft survival, and infection were also compared between groups. A multivariate Cox regression analysis was performed to investigate the influential factors associated with clinically-suspected acute rejection and graft survival. RESULTS: The rATG group had a higher panel reactive antibody (PRA) score and more complete HLA mismatches than the IL2-RA group (both P < 0.001). The incidences of clinically-suspected acute rejection (9.8% vs. 8.8%; P = 0.832) and dn-DSA formation (4.9% vs. 5.4%, P = 0.44) were not significantly different between groups. Kaplan-Meier curve analysis demonstrated that the graft survivals of two groups were comparable (P = 0.857). After adjusting for patients' age, sex, PRA, HLA mismatch confounders, and the use of corticoids, the multivariate Cox regression analysis showed that methods of induction therapy were not associated with clinically-suspected acute rejection and graft survival (both P > 0.05). The incidences of complications (infections, pneumonia, liver injury and myelosuppression) were all comparable between groups (all P > 0.05). CONCLUSIONS: These results suggested that rATG could be a safe and efficient immunosuppressant when used in a Chinese recipient population with a higher immunological risk in living donor renal transplantation.


Assuntos
Soro Antilinfocitário/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Transplante de Rim/tendências , Doadores Vivos , Receptores de Interleucina-2/antagonistas & inibidores , Adolescente , Adulto , Animais , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/fisiologia , Humanos , Quimioterapia de Indução/métodos , Quimioterapia de Indução/tendências , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Coelhos , Estudos Retrospectivos , Adulto Jovem
20.
Medicine (Baltimore) ; 98(7): e14470, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762766

RESUMO

RATIONALE: Intravascular large B-cell lymphoma (IVLBCL) is a type of malignant lymphoma in which neoplastic B cells proliferate selectively within the lumina of small- and medium-sized vessels. Patients with IVLBCL frequently develop neurological manifestations during their disease course. Patients are known to often develop various neurological manifestations, but there are only a few reports of IVLBCL whose initial symptoms are deafness and/or disequilibrium. PATIENT CONCERNS: A 66-year-old Japanese man was provisionally diagnosed with sudden sensorineural hearing loss. Administration of prednisolone did not improve his symptoms, and then he experienced amaurosis fugax. Magnetic resonance imaging (MRI) showed multiple brain infarcts, so he was administered antithrombotic drugs. Nevertheless, he experienced recurrent strokes, became irritable, and had visual hallucinations. He was emergently admitted to our hospital with disturbance of consciousness. DIAGNOSIS: Blood tests showed elevation of lactose dehydrogenase and soluble interleukin-2 receptor. Cranial MR diffusion-weighted imaging showed multiple lesions bilaterally in the cerebral white matter and cortex, posterior limbs of the internal capsule, and cerebellar hemispheres, which were hypointense on apparent diffusion coefficient maps. Hyperintense lesions were detected bilaterally in the cerebral white matter and basal ganglia on both T2-weighted imaging and fluid-attenuated inversion recovery imaging. Contrast-enhanced brain MRI demonstrated contrast-enhancing high-signal lesions along the cerebral cortex. Brain biopsy revealed a diagnosis of IVLBCL. INTERVENTIONS: The patient could not receive chemotherapy because of his poor general condition. Therefore, we administered high-dose methylprednisolone (mPSL) pulse therapy. OUTCOMES: There was little improvement in consciousness levels after the high-dose mPSL pulse therapy. On the forty-ninth day of hospitalization, he was transferred to another hospital to receive supportive care. LESSONS: IVLBCL should be regarded as an important differential diagnosis of hearing loss and dizziness. Most importantly, if the symptoms are fluctuant and steroid therapy is not effective, biopsy should be considered as early as possible.


Assuntos
Tontura/etiologia , Perda Auditiva/etiologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/fisiopatologia , Idoso , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Oxirredutases/sangue , Receptores de Interleucina-2/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA