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1.
Rinsho Ketsueki ; 60(9): 1199-1204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597844

RESUMO

The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.


Assuntos
Linfoma Folicular/terapia , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20 , Humanos , Imunoterapia , Lenalidomida/uso terapêutico , Rituximab/uso terapêutico
2.
Wiad Lek ; 72(9 cz 2): 1723-1726, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622254

RESUMO

OBJECTIVE: Introduction: Chronic hyperglycemia as the main link in DM pathogenesis leads to systemic vessels and nerves lesion with chronic bone complications development consequently. The aim: To evaluate influence of hyperglycemia on reparative osteogenesis after perforated tibial fracture in rats. PATIENTS AND METHODS: Materials and methods: A total of 30 white adult rats were subdivided into two groups: 15 healthy rats in Group 1 (control) and 15 rats with alloxan induced hyperglycemia in Group 2 (investigated) and were carried out of experiment on the 10th, 20th and 30th day after the fracture. Hyperglycemia in rats was verificated as the postprandial glycemic rate ≥ 8,0 mmol/l. Tibia diaphysis fracture was modeled by a cylindrical defect with a diameter of 2 mm with portable frezer. Morphological evaluation. A complex morphological studies included histological, morphometric and immunohistochemical examination. RESULTS: Results: This is confirmed by an increase in MMP-9 expression in connective tissue, a decrease in TGF-ß expression in all phases, an increase in the expression of CD3 and CD20 and a marked decrease in the expression of all vascular markers. During hyperglycemia, incomplete blood supply to the tissues occurs, necrosis of bone and soft tissues develop in the area of the fracture, the reparative reaction slows down considerably and manifests itself in the development of fibrous and, less commonly, cartilage tissue. CONCLUSION: Conclusions: In hyperglycemia rats, there was a delay in the callus formation, a decrease in proliferation and ossification, and a slowdown in the processes of angiogenesis.


Assuntos
Diabetes Mellitus/fisiopatologia , Osteogênese , Fraturas da Tíbia/complicações , Animais , Antígenos CD20/metabolismo , Osso e Ossos , Calo Ósseo , Complexo CD3/metabolismo , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica , Ratos , Fator de Crescimento Transformador beta/metabolismo
3.
Cancer Immunol Immunother ; 68(10): 1561-1572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494742

RESUMO

Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.


Assuntos
Antígenos CD20/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfoma/tratamento farmacológico , Animais , Feminino , Cadeias HLA-DRB1/imunologia , Humanos , Interferon gama/biossíntese , Linfoma/imunologia , Camundongos , Rituximab/uso terapêutico
4.
Cancer Immunol Immunother ; 68(10): 1573-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31511925

RESUMO

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.


Assuntos
Antígeno B7-H1/fisiologia , Fibromatose Agressiva/imunologia , Tolerância Imunológica , Adolescente , Adulto , Idoso , Antígenos CD20/análise , Ligante CD27/análise , Feminino , Fibromatose Agressiva/patologia , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral , Adulto Jovem
5.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
6.
Medicine (Baltimore) ; 98(25): e15944, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232925

RESUMO

OBJECTIVE: To test the safety of ublituximab, a B cell depleting agent, as add-on therapy in the acute treatment of relapses of neuromyelitis optica spectrum disorder. METHODS: We conducted an open-label phase 1b safety and proof-of-concept trial in 5 subjects with aquaporin-4 (AQP4)-immunoglobulin G (IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily intravenous methylprednisolone, we infused a single dose of 450 mg of ublituximab within 5 days of relapse onset. The primary outcome measure was safety, and the secondary efficacy measures included change in Expanded Disability Status Scale (EDSS), durability of remission and B cell counts. RESULTS: Five NMOSD subjects were enrolled, 4 of whom presented with acute transverse myelitis and 1 with acute optic neuritis. Ublituximab proved to be safe in all 5 NMOSD subjects, with no serious adverse events recorded. There were no opportunistic infections in any of the subjects; however, 1 subject experienced a transient leukopenia. EDSS scores dropped from a median of 6.5 on admission to 4.0 on 90-day follow up. Two subjects did not achieve total B cell depletion and relapsed within 3 months. CONCLUSIONS: Ublituximab is a safe add-on therapy for NMOSD patients presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit on durability of remission when B cell depletion is achieved. A placebo-controlled trial is necessary to confirm these findings. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with NMOSD with acute transverse myelitis or optic neuritis, ublituximab is safe and may improve neurological outcome.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20 , Metilprednisolona/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metilprednisolona/administração & dosagem , Neuromielite Óptica/patologia , Projetos Piloto , Recidiva , Resultado do Tratamento
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 839-843, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204941

RESUMO

OBJECTIVE: To investigate the clinical characteristics and therapeutic responte of patients with B-CLPD mainly manifested as cytopenia, so as to deeply understand this disease. METHODS: The clinical data of 13 B-CLPD patients with hematocytopenia as main manifestation, and the absolute count of lymphocytes<5×109/L, absence of hepatosplenic lymph-nodes and extramedullary invasion tin our department fron 2003 to 2018 were analyzed retrospectively. The clinical characteristics, therapeutic efficacy and adverse reactions of 3 patients were summarized. RESULTS: The median age of patients was 59 (43-76) years old, the median of lymphocyte was 1.86 (0.69-4.8) ×109/L, the levels of LDH and ß2-microglubulin were normal in most patients, the monolineage and multilencage hematopoietic failure of different degrees existed in most all patients. The lymphocyte ratio in patients was 18.5%-94.0%, CD20 was positive in all patients, and yet the CD5-positive and CD-negative existed in 7 and 6 cases respectively. There was no significant difference in ratio of lymphocyte invasion among different immunophemtype. The FISH detection showed that there were no high risk genetic types. 92.3% of patients received rituximab treatment, most of them received chemotherapy of rituximab combined with C0P/CHOP like regimen, only 2 patients received fludarabine for comparatively short course. The analysis indicated that 8 out of 13 patients showed a certain theropeutic efficacy, however the drug-related hematopoietic suppression occurred in both 2 patients treated with fludarabin. CONCLUSIONS: The B-CLPD accompanied with hematocytopenia often displays bone marrow hypohematopoiesis of different degree and easily confuses with the congenital and acquired hemotopoietic faiture diseases. The rituximab treatment may be more appropreate for these patients, but for patients received chemotherapy containing fludarabin, the persistant hematopoietic failure must be especially watched out.


Assuntos
Transtornos Linfoproliferativos , Adulto , Idoso , Antígenos CD20 , Protocolos de Quimioterapia Combinada Antineoplásica , Linfócitos B , Ciclofosfamida , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab
8.
Indian J Ophthalmol ; 67(7): 1217-1219, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31238472

RESUMO

Vogt-Koyanagi-Harada (VKH) disease is a systemic disorder causing bilateral panuveitis. Histopathological documentation along with molecular diagnostic evidence in VKH eye is a rarity. We present a 46-year-old woman with VKH with several ocular complications and subsequently enucleation of the right eye was done because of painful blind eye. Patient had clinical complications of VKH and some of the complications were observed in histopathology. Pathology of the case showed nongranulomatous uveitis, indicating the disease in chronic recurrent stage. Immunohistochemistry showed predominant T-cell involvement in this case. The case showed clinicopathological and immunohistochemistry correlation in a case of VKH disease.


Assuntos
Antígenos CD20/análise , Complexo CD3/análise , Imuno-Histoquímica/métodos , Pan-Uveíte/diagnóstico , Síndrome Uveomeningoencefálica/complicações , Enucleação Ocular , Feminino , Humanos , Pessoa de Meia-Idade , Pan-Uveíte/etiologia , Pan-Uveíte/cirurgia , Tomografia de Coerência Óptica , Síndrome Uveomeningoencefálica/diagnóstico , Síndrome Uveomeningoencefálica/imunologia
9.
Hematol Oncol ; 37 Suppl 1: 101-104, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187537

RESUMO

In recent years, many new antibodies, either naked or armed with toxin or radionuclides have been investigated to enhance the field of active agents directed against already identified ("old") targets. This was particularly the case for the antigens CD19 and CD20 but also some other ones. The success of these developments has been variable and underlines the need to better characterize the mode of action of these molecules. Combinations studies of these new agents with other molecules, in particular those with an immunomodulatory potential, are also currently developed with some promising results.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Antígenos CD19 , Antígenos CD20 , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunomodulação/efeitos dos fármacos , Neoplasias/etiologia , Neoplasias/metabolismo , Tetraspaninas
10.
Autoimmun Rev ; 18(7): 665-672, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059839

RESUMO

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T cells. Increasing evidence, however, suggests the fundamental role of B cells in the pathogenesis and development of the disease. Recently, anti-CD20 B cell-based therapies have demonstrated impressive and somewhat surprising results in MS, showing profound anti-inflammatory effects with a favorable risk-benefit ratio. Moreover, for the first time in the MS therapeutic scenario, the anti-CD20 monoclonal antibody ocrelizumab has been granted for the treatment of the primary progressive form of the disease. In this review, we provide a brief overview about anti-CD20 B cell-based therapies in MS, in the perspective of their influence on the future management of the disease, and of their possible positioning in a new wider therapeutic scenario.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Esclerose Múltipla/imunologia , Animais , Humanos , Esclerose Múltipla/terapia
11.
Croat Med J ; 60(2): 87-98, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044580

RESUMO

Increasing evidence suggests that B cells contribute both to the regulation of normal autoimmunity and to the pathogenesis of immune mediated diseases, including multiple sclerosis (MS). B cells in MS are skewed toward a pro-inflammatory profile, and contribute to MS pathogenesis by antibody production, antigen presentation, T cells stimulation and activation, driving autoproliferation of brain-homing autoreactive CD4+ T cells, production of pro-inflammatory cytokines, and formation of ectopic meningeal germinal centers that drive cortical pathology and contribute to neurological disability. The recent interest in the key role of B cells in MS has been evoked by the profound anti-inflammatory effects of rituximab, a chimeric monoclonal antibody (mAb) targeting the B cell surface marker CD20, observed in relapsing-remitting MS. This has been reaffirmed by clinical trials with less immunogenic and more potent B cell-depleting mAbs targeting CD20 - ocrelizumab, ofatumumab and ublituximab. Ocrelizumab is also the first disease-modifying drug that has shown efficacy in primary-progressive MS, and is currently approved for both indications. Another promising approach is the inhibition of Bruton's tyrosine kinase, a key enzyme that mediates B cell activation and survival, by agents such as evobrutinib. On the other hand, targeting B cell cytokines with the fusion protein atacicept increased MS activity, highlighting the complex and not fully understood role of B cells and humoral immunity in MS. Finally, all other approved therapies for MS, some of which have been designed to target T cells, have some effects on the frequency, phenotype, or homing of B cells, which may contribute to their therapeutic activity.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/fisiologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/imunologia , Rituximab/uso terapêutico , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Fatores Imunológicos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Proteínas Recombinantes de Fusão , Rituximab/farmacologia
12.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003532

RESUMO

Antigen-mimicking peptide (mimotope)-based vaccines are one of the most promising forms of active-immunotherapy. The main drawback of this approach is that it induces antibodies that react poorly with the nominal antigen. The aim of this study was to investigate the molecular basis underlying the weak antibody response induced against the naïve protein after peptide vaccination. For this purpose, we analyzed the fine specificity of monoclonal antibodies (mAb) elicited with a 13-mer linear peptide, complementary to theantigen-combining site of the anti-CD20 mAb, Rituximab, in BALB/c mice. Anti-peptide mAb competed with Rituximab for peptide binding. Even so, they recognized a different antigenic motif from the one recognized by Rituximab. This explains their lack of reactivity with membrane (naïve) CD20. These data indicate that even on a short peptide the immunogenic and antigenic motifs may be different. These findings highlight an additional mechanism for epitope spreading and should be taken into account when designing peptides for vaccine purposes.


Assuntos
Anticorpos Monoclonais/genética , Antígenos CD20/imunologia , Peptídeos/genética , Rituximab/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Murinos/genética , Anticorpos Monoclonais Murinos/imunologia , Antígenos CD20/genética , Sítios de Ligação de Anticorpos/genética , Epitopos/genética , Epitopos/imunologia , Humanos , Camundongos , Biblioteca de Peptídeos , Peptídeos/imunologia , Rituximab/genética , Vacinação/métodos , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia
13.
Indian J Pathol Microbiol ; 62(2): 316-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971566

RESUMO

Pagetoid reticulosis is an indolent cutaneous T-cell lymphoma and presents as erythema or plaque with a well-defined border on the distal areas of the extremities. Immunophenotypic studies show that in most cases, neoplastic lymphocytes are positive for CD4, whereas CD20 and CD30 double positivity was rarely reported. In this paper, we report an 80-year-old woman who presented with erythema on the extremities for 3 years. Skin biopsy on the right forearm was performed. Histopathologically, the erythematous lesions were characterized by atypical lymphocytes with significant epidermotropism. Immunohistochemical staining showed high proliferation as evidenced by high Ki-67 index and that the tumor cells were positive for CD20 and CD30 but negative for CD7 and CD56. The patient was treated with one cycle of radiotherapy and is currently doing well.


Assuntos
Antígenos CD20/genética , Antígeno Ki-1/genética , Reticulose Pagetoide/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso de 80 Anos ou mais , Biópsia , Eritema , Feminino , Humanos , Imunofenotipagem , Linfócitos , Linfoma Cutâneo de Células T/diagnóstico , Reticulose Pagetoide/radioterapia , Pele/patologia , Neoplasias Cutâneas/radioterapia , Resultado do Tratamento
14.
Medicine (Baltimore) ; 98(15): e15204, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985716

RESUMO

RATIONALE: Second diffuse large B-cell lymphoma (DLBCL) after treatment of acute lymphoblastic leukemia (ALL) is uncommon. To our knowledge, primary middle ear DLBCL which presents CD20-negative and coexpression of MYC and BCL-2 has not been reported yet. PATIENT CONCERNS: A 20-year-old Chinese man complained fever and weakness for 2 months. Subsequently bone marrow morphology and flow cytometry immunophenotype suggested ALL. Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. Then the mass resection was performed for biopsy and immunohistochemistry examination. DIAGNOSIS: The mass was diagnosed as DLBCL which was negative for CD20 and double expression of MYC and BCL-2. INTERVENTIONS: Chemotherapy. OUTCOMES: The patient eventually gave up and died of severe infection. LESSONS: Although intensive chemotherapy has markedly improved the survival of ALL, more and more secondary cancers have been reported. In addition, primary middle ear lymphoma is much rare; hence, it is easy to be misdiagnosed. Furthermore, DLBCL with negative CD20 and double expression of MYC and BCL-2 is aggressive, which is characterized by chemotherapy resistance and inferior survival rates. We discuss this case aiming at raising awareness of tumors secondary to ALL and exploring the appropriate treatment options for the rare DLBCL.


Assuntos
Neoplasias da Orelha/diagnóstico , Orelha Média , Linfoma Difuso de Grandes Células B/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Antígenos CD20/análise , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Neoplasias da Orelha/química , Neoplasias da Orelha/tratamento farmacológico , Neoplasias da Orelha/patologia , Evolução Fatal , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
15.
Biomed Pharmacother ; 114: 108804, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909146

RESUMO

B lymphocytes have been shown to contribute to autoimmune diseases via producing antibodies and proinflammatory cytokines. Depletion of B cells by blocking CD20 can inhibit these diseases. Here we examined whether an antibody against CD20, rituximab (RTX) (Rituxan@), used clinically in oncology could have similar anti-inflammatory effects in cardiac remodeling and heart failure (HF) in mice. Cardiac remodeling was established by pressure overload induced by transverse aortic constriction (TAC). Wild-type (WT) male C57BL/6 J mice were subjected to pressure overload by using transverse aortic constriction and then received RTX for 4 weeks. Administration of RTX markedly improves in vivo heart function, and suppressed heart chamber dilation, myocyte hypertrophy, fibrosis and oxidative stress in mice after TAC operation. RTX treatment also reversed established hypertrophic remodeling induced by TAC. Moreover, TAC-induced activation of multiple signaling pathways including calcineurin A, ERK1/2, STAT3, TGFß/Smad2/3 and IKKα/ß/NF-kB were remarkably attenuated in RTX-treated hearts compared with controls. These inhibitory effects of RTX were associated with inhibition of proinflammatory cytokine expression and Th2 cytokine-mediated IgG production from B cells. In conclusion, this study identifies that administration of RTX can inhibit pressure overload-induced cardiac remodeling and dysfunction in mice, and suggest that RTX may be a promising drug for treating hypertrophic disease.


Assuntos
Linfócitos B/efeitos dos fármacos , Coração/efeitos dos fármacos , Rituximab/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Blood ; 133(10): 1003-1004, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846506
17.
J Nippon Med Sch ; 86(1): 15-21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918150

RESUMO

BACKGROUND: Intratumoral lymphocytes are a defining feature of spiradenoma; however, there have only been a few reports on the phenotypic features of non-epithelial cells. Spiradenomas also contain numerous cells positive for S-100 protein and the nature of these cells is still controversial. METHODS: We performed a clinicopathological and immunohistochemical study of ten cases of spiradenoma. RESULTS: The study included seven men and three women. On histopathological examination, spiradenoma could be divided into two types: the vascular proliferating (VP) type (five cases) that featured granulation tissue with edema, vascular proliferation, and inflammatory cell infiltration into the stroma, and the common type (five cases), which did not include any of the aforementioned features. Immunohistochemical staining demonstrated a large number of cells positive for S-100 protein. These included cells with large pale nuclei, dendritic cells, and a few cells with small dark nuclei that were also positive for α-smooth muscle actin. Most of the cells infiltrating the parenchymata of these lesions were CD3-positive. The proportions of CD4-positive and CD8-positive cells were almost equal or CD8-positive cells were predominant. CD20+ cells were observed in five spiradenomas. In painful lesions, there were numerous nerve fibers near the tumor. CONCLUSIONS: In spiradenoma, CD3+ T cells were mainly seen in the parenchyma and CD8+ cells were predominant over CD4+ cells in most cases. CD20+ cells showed focal infiltration of the parenchyma and stroma, especially in VP-type lesions. S-100 protein-positive cells in spiradenoma contained not only Langerhans cells, but also cells with myoepithelial differentiation.


Assuntos
Adenoma de Glândula Sudorípara/metabolismo , Adenoma de Glândula Sudorípara/patologia , Proteínas S100/metabolismo , Neoplasias das Glândulas Sudoríparas/metabolismo , Neoplasias das Glândulas Sudoríparas/patologia , Actinas/metabolismo , Adenoma de Glândula Sudorípara/classificação , Adulto , Idoso , Antígenos CD20 , Complexo CD3 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Feminino , Humanos , Imuno-Histoquímica , Células de Langerhans , Masculino , Pessoa de Meia-Idade , Neoplasias das Glândulas Sudoríparas/classificação
18.
Cancer Immunol Immunother ; 68(6): 927-936, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30879106

RESUMO

BACKGROUND: Immune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized. METHODS: Marker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics. RESULTS: B cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10low, PTGS2low or CD163low tumor microenvironment according to the transcriptomic data. IL10 levels consistently correlated with the M2-like macrophage marker CD163, which also defined the majority of macrophages. A polarization of these cells toward a pro-tumoral phenotype was further supported by lack of correlation between CD163 and M1 markers like NOS2, as well as by low abundance of CD80 positive cells in tissue. CONCLUSIONS: Analysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Macrófagos/imunologia , Sarcoma/imunologia , Neoplasias de Tecidos Moles/imunologia , Transcriptoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/genética , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem
19.
J Biol Chem ; 294(16): 6294-6305, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782846

RESUMO

Several antibody-targeting cancer immunotherapies have been developed based on T cell activation at the target cells. One of the most potent activators of T cells are bacterial superantigens, which bind to major histocompatibility complex class II on antigen-presenting cells and activate T cells through T cell receptor. Strong T cell activation is also one of the main weaknesses of this strategy as it may lead to systemic T cell activation. To overcome the limitation of conventional antibody-superantigen fusion proteins, we have split a superantigen into two fragments, individually inactive, until both fragments came into close proximity and reassembled into a biologically active form capable of activating T cell response. A screening method based on fusion between SEA and coiled-coil heterodimers was developed that enabled detection of functional split SEA designs. The split SEA design that demonstrated efficacy in fusion with coiled-coil dimer forming polypeptides was fused to a single chain antibody specific for tumor antigen CD20. This design selectively activated T cells by split SEA-scFv fusion binding to target cells.


Assuntos
Enterotoxinas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Anticorpos de Cadeia Única/farmacocinética , Superantígenos/farmacologia , Linfócitos T/imunologia , Antígenos CD20/imunologia , Linhagem Celular Tumoral , Enterotoxinas/genética , Células HEK293 , Humanos , Anticorpos de Cadeia Única/genética , Superantígenos/genética , Linfócitos T/patologia
20.
Parasitol Res ; 118(4): 1325-1329, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747295

RESUMO

Chagas disease is caused by Trypanosoma cruzi and remains one of the most neglected diseases in Latin America. One of its clinical forms is Chagas megacolon. Despite being known for more than half a century, detailed causes are still obscure. Recent evidence indicates a close relationship between the immune system and the enteric nervous system in the etiology of chagasic megacolon pathology. It is believed that low expression of the 5-HT3A serotonin receptor on lymphocytes could be linked to megacolon development. To test this hypothesis, this work investigated the distribution of CD4, CD8, and CD20 lymphocytes and their 5-HT3A receptor expression. The results demonstrated that Chagas patients without megacolon present a higher expression of the 5-HT3A receptor in all analyzed lymphocytes compared with Chagas patients with megacolon. These data suggest that the high expression of this receptor may lead to immunomodulation and prevent the development of Chagas megacolon.


Assuntos
Doença de Chagas/patologia , Sistema Nervoso Entérico/patologia , Sistema Imunitário/patologia , Megacolo/patologia , Receptores 5-HT3 de Serotonina/metabolismo , Antígenos CD20/análise , Antígenos CD4/análise , Antígenos CD8/análise , Humanos , Linfócitos/metabolismo , Linfócitos/parasitologia , Megacolo/parasitologia , Pessoa de Meia-Idade , Serotonina , Trypanosoma cruzi/patogenicidade
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