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[PMID]:29350259
[Au] Autor:Zhu X; Zhang J; Wang Q; Fu H; Chang Y; Kong Y; Lv M; Xu L; Liu K; Huang X; Zhang X
[Ad] Endereço:Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China.
[Ti] Título:Diminished expression of ß2-GPI is associated with a reduced ability to mitigate complement activation in anti-GPIIb/IIIa-mediated immune thrombocytopenia.
[So] Source:Ann Hematol;97(4):641-654, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Anti-GPIIb/IIIa-mediated complement activation has been reported to be important in the pathogenesis of immune thrombocytopenia (ITP). However, the role of the complement system and the involved regulatory mechanism remain equivocal. Beta2-glycoprotein I (ß2-GPI), known as the main target for antiphospholipid autoantibodies, has been demonstrated as a complement regulator. Here, we investigated the complement-regulatory role of ß2-GPI in anti-GPIIb/IIIa-mediated ITP. Plasma complement activation and enhanced complement activation capacity (CAC) were found in ITP patients with anti-GPIIb/IIIa antibodies in vivo and in vitro. Diminished plasma levels of ß2-GPI were shown in patients of this group, which was inversely correlated with C5b-9 deposition. C5b-9 generation was inhibited by approximate physiological concentrations of ß2-GPI, in a dose-dependent manner. Inhibition of C3a generation by ß2-GPI and the existence of ß2-GPI/C3 complexes in plasma indicated a regulation on the level of the C3 convertase. Furthermore, ß2-GPI down-regulated the phosphorylation levels of c-Jun N-terminal kinase (JNK) and cleavage of BH3 interacting domain death agonist (Bid) and ultimately harbored platelet lysis. Our findings may provide a novel link between diminished plasma levels of ß2-GPI and enhanced complement activation, indicating ß2-GPI as a potential diagnostic biomarker and therapeutic target in the treatment of anti-GPIIb/IIIa-mediated ITP.
[Mh] Termos MeSH primário: Ativação do Complemento
Regulação para Baixo
Isoanticorpos/metabolismo
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores
Púrpura Trombocitopênica Idiopática/metabolismo
beta 2-Glicoproteína I/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Biomarcadores/sangue
Plaquetas/imunologia
Plaquetas/metabolismo
Plaquetas/patologia
China/epidemiologia
Convertases de Complemento C3-C5/metabolismo
Complemento C3a/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Púrpura Trombocitopênica Idiopática/imunologia
Púrpura Trombocitopênica Idiopática/patologia
Púrpura Trombocitopênica Idiopática/fisiopatologia
Risco
Trombocitopenia/sangue
Trombocitopenia/imunologia
Trombocitopenia/metabolismo
Trombose/epidemiologia
Trombose/etiologia
Adulto Jovem
beta 2-Glicoproteína I/sangue
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Isoantibodies); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (beta 2-Glycoprotein I); 0 (glycoprotein receptor GPIb-IX); 80295-42-7 (Complement C3a); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3215-3


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[PMID]:29266058
[Au] Autor:Lan JH; Tinckam K
[Ad] Endereço:Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
[Ti] Título:Clinical Utility of Complement Dependent Assays in Kidney Transplantation.
[So] Source:Transplantation;102(1S Suppl 1):S14-S22, 2018 01.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Formation of antibodies against polymorphic HLA molecules on donor endothelium is central to the pathogenesis of antibody-mediated rejection, the dominant cause of long-term kidney allograft loss. Although introduction of the single-antigen bead assay has greatly facilitated the immune risk assessment of transplant recipients, it is recognized that not all IgG HLA antibodies detected using this method are equally relevant. In recent years, novel assays (C4d, C1q, C3d) have been developed to interrogate the complement-activating potential of anti-HLA antibodies in vitro, with the hypothesis that complement-fixing antibodies are more immediately injurious to the graft compared with noncomplement-binding antibodies. Although initial studies demonstrated the potential of these assays to risk-stratify antibodies beyond the conventional limited metric of mean fluorescence intensity values, new data from recent analyses challenge some of these early findings. In this review, we examine the technical aspects of these assays and key studies that evaluated the discriminant capacity of these tests to predict numerous outcomes in kidney transplantation. We discuss conflicting data and emerging controversies in the context of recent experimental evidence which offer new insights into the major factors that influence complement activation. Finally, we provide our perspective on the current role and utility of complement diagnostic assays as 1 variable in the multifactorial risk assessment and management of kidney transplant recipients.
[Mh] Termos MeSH primário: Ativação do Complemento/imunologia
Proteínas do Sistema Complemento/imunologia
Rejeição de Enxerto/imunologia
Antígenos HLA/imunologia
Teste de Histocompatibilidade/métodos
Isoanticorpos/metabolismo
Transplante de Rim
[Mh] Termos MeSH secundário: Biomarcadores/metabolismo
Rejeição de Enxerto/prevenção & controle
Seres Humanos
Isoanticorpos/imunologia
Medição de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); 0 (HLA Antigens); 0 (Isoantibodies); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001819


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[PMID]:29266057
[Au] Autor:Valenzuela NM; Schaub S
[Ad] Endereço:UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA.
[Ti] Título:The Biology of IgG Subclasses and Their Clinical Relevance to Transplantation.
[So] Source:Transplantation;102(1S Suppl 1):S7-S13, 2018 01.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immunoglobulin G (IgG) is the dominant immunoglobulin and can be divided into 4 distinct subclasses. The evolution of IgG subclass switches is regulated by interaction with T cells and follows a 1-way direction (IgG3 → IgG1 → IgG2 → IgG4). Based on their structure, the 4 IgG subclasses can initiate different effector function such as complement activation, recruitment of various cells by Fc receptors, and agonistic signaling. Using current assays for HLA antibody detection as a template and replacing the generic reporter antibody with IgG subclass-specific reporter antibodies, it is possible to investigate the IgG subclasses of HLA antibodies. There are 15 different IgG subclass compositions possible. Based on the capability to activate the complement system and the class switch direction, 3 arbitrary patterns can be defined (ie, only complement-binding subclasses [IgG3 and/or IgG1], expansion to noncomplement-binding subclasses [IgG3 and/or IgG1 plus IgG2 and/or IgG4], and switch to noncomplement-binding subclasses [IgG2 and/or IgG4]). The latter group accounts for less than 5%, whereas the former 2 groups have a similar prevalence close to 50%. In the past 5 years, several studies correlated the IgG subclass pattern with occurrence of antibody-mediated rejection and allograft outcomes. Because of differences of the used IgG subclass assay, the time point of analyses, and the definition of outcomes, a clear picture has not emerged yet. Future needs are standardization of the assay, a more detailed knowledge of the initiated effector functions, and more well-designed clinical studies also looking at changes of the IgG subclass pattern over time.
[Mh] Termos MeSH primário: Antígenos HLA/imunologia
Teste de Histocompatibilidade
Switching de Imunoglobulina/imunologia
Imunoglobulina G/imunologia
Isoanticorpos/imunologia
Transplante de Órgãos
[Mh] Termos MeSH secundário: Ativação do Complemento/imunologia
Seres Humanos
Imunoglobulina G/classificação
Imunoglobulina G/genética
Isoanticorpos/classificação
Isoanticorpos/genética
Receptores Fc/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (HLA Antigens); 0 (Immunoglobulin G); 0 (Isoantibodies); 0 (Receptors, Fc)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001816


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[PMID]:29199277
[Au] Autor:Ricklin D; Mastellos DC; Reis ES; Lambris JD
[Ad] Endereço:Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
[Ti] Título:The renaissance of complement therapeutics.
[So] Source:Nat Rev Nephrol;14(1):26-47, 2018 Jan.
[Is] ISSN:1759-507X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The increasing number of clinical conditions that involve a pathological contribution from the complement system - many of which affect the kidneys - has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.
[Mh] Termos MeSH primário: Inativadores do Complemento/uso terapêutico
Proteínas do Sistema Complemento/imunologia
Rejeição de Enxerto/tratamento farmacológico
Nefropatias/tratamento farmacológico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/imunologia
Descoberta de Drogas
Seres Humanos
Inflamação
Nefropatias/imunologia
Terapia de Alvo Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement Inactivating Agents); 9007-36-7 (Complement System Proteins); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180210
[Lr] Data última revisão:
180210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1038/nrneph.2017.156


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[PMID]:27771173
[Au] Autor:Farkas P; Csuka D; Mikes B; Sinkovits G; Réti M; Németh E; Rácz K; Madách K; Gergely M; Demeter J; Prohászka Z
[Ad] Endereço:3rd Department of Internal Medicine, Research Laboratory and Füst György Complement Diagnostic Laboratory, Semmelweis University, Budapest, Hungary.
[Ti] Título:Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies.
[So] Source:Immunobiology;222(2):119-127, 2017 02.
[Is] ISSN:1878-3279
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The secondary forms of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (secondary TMA) emerge as complications of coexisting diseases. OBJECTIVES: We hypothesized that secondary TMA could be characterized by the presence of relative ADAMTS13 deficiency and complement activation, and this relationship may have a prognostic value for outcome. PATIENTS AND METHODS: Fifty-three patients with thrombotic microangiopathy (TMA) and coexisting disease (such as malignancies, sepsis, heart surgery with extracorporeal circulation, solid organ transplantation, systemic autoimmune disorders), 41 patient controls, and 34 healthy controls were enrolled in our case-control study with 30days follow-up. Complement profile (from serum) and activation products, von Willebrand factor (VWF, from EDTA plasma), and ADAMTS13 activity were determined. RESULTS: ADAMTS13 activity was reduced, while VWF level was elevated in secondary TMA patients. The activity of the classical, lectin and alternative pathways, as well as the levels of C3, C4, and Factor H were significantly lower in secondary TMA patients, and were accompanied by high activation product levels (C3a and sC5b-9). Factor H concentration correlated to relative ADAMTS13 deficiency (i.e. VWF/ADAMTS13 ratio (r=-0.368, p=0.019)). 28/53 patients (53%) died during the follow-up period. Increased sC5b-9, C3a, and C reactive protein levels were all associated with a poor patient outcome. CONCLUSIONS: Our results indicate that the secondary TMA syndrome and its poor outcome is characterized by relative ADAMTS13 deficiency, inflammation, and complement activation with consumption via the classical and alternative pathways. It is yet to be determined whether complement inhibition could be a possible therapeutic option for patients with secondary TMA.
[Mh] Termos MeSH primário: Proteína ADAMTS13/deficiência
Ativação do Complemento/imunologia
Proteínas do Sistema Complemento/imunologia
Inflamação/complicações
Microangiopatias Trombóticas/etiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores
Estudos de Casos e Controles
Criança
Pré-Escolar
Comorbidade
Ativação do Complemento/genética
Proteínas do Sistema Complemento/metabolismo
Feminino
Seres Humanos
Masculino
Meia-Idade
Prognóstico
Modelos de Riscos Proporcionais
Microangiopatias Trombóticas/diagnóstico
Microangiopatias Trombóticas/metabolismo
Microangiopatias Trombóticas/mortalidade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 9007-36-7 (Complement System Proteins); EC 3.4.24.87 (ADAMTS13 Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180125
[Lr] Data última revisão:
180125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29242207
[Au] Autor:Schmidt CQ; Verschoor A
[Ad] Endereço:ULM UNIVERSITY.
[Ti] Título:Complement and coagulation: so close, yet so far.
[So] Source:Blood;130(24):2581-2582, 2017 12 14.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Coagulação Sanguínea
Proteínas do Sistema Complemento
[Mh] Termos MeSH secundário: Ativação do Complemento
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-10-811943


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[PMID]:27775697
[Au] Autor:Dhakal P; Bhatt VR
[Ad] Endereço:Department of Medicine, Michigan State University, East Lansing, MI, USA.
[Ti] Título:Is complement blockade an acceptable therapeutic strategy for hematopoietic cell transplant-associated thrombotic microangiopathy?
[So] Source:Bone Marrow Transplant;52(3):352-356, 2017 Mar.
[Is] ISSN:1476-5365
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development. Complement blockade using eculizumab has shown some promising rates of hematologic responses, however, survival may still be poor. Early discontinuation of calcineurin inhibitor where feasible, use of eculizumab, aggressive infection prophylaxis, close monitoring and early treatment of potential complications including GvHD and organ failure may improve outcomes. A number of complement inhibitors are in the development and may change treatment paradigm. Future studies are important to better understand TA-TMA as a disease process and may aim to confirm the role of complement activation in TA-TMA, enhance diagnostic strategy, determine therapeutic approaches and strategies to reduce the risk of other complications particularly infection and GvHD.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/efeitos dos fármacos
Proteínas do Sistema Complemento/metabolismo
Transplante de Células-Tronco Hematopoéticas
Microangiopatias Trombóticas/tratamento farmacológico
[Mh] Termos MeSH secundário: Aloenxertos
Inibidores de Calcineurina/uso terapêutico
Doença Enxerto-Hospedeiro/tratamento farmacológico
Doença Enxerto-Hospedeiro/etiologia
Doença Enxerto-Hospedeiro/metabolismo
Seres Humanos
Controle de Infecções
Microangiopatias Trombóticas/etiologia
Microangiopatias Trombóticas/metabolismo
Microangiopatias Trombóticas/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Calcineurin Inhibitors); 9007-36-7 (Complement System Proteins); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.1038/bmt.2016.253


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[PMID]:28951216
[Au] Autor:Wang H; Li N; Zhu C; Shi S; Jin H; Wang S
[Ad] Endereço:The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China.
[Ti] Título:Anti-complementary activity of two homogeneous polysaccharides from Eclipta prostrata.
[So] Source:Biochem Biophys Res Commun;493(2):887-893, 2017 Nov 18.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement-mediated inflammation and tissue damage is an important drive to pathology in autoimmune diseases, targeting inhibit the complement activation is promising treatment strategy for these diseases. We performed anticomplement activity-guided fractionation of the water extract of Eclipta prostrata by ion-exchange and size-exclusion chromatography, yielding two bioactive polysaccharides EAP20-1 and EAP20-2. The molecular weights of EAP20-1 and EAP20-2 were respectively calculated to be 5.2 kDa and 6.3 kDa by HPGPC, both polysaccharides was composed by d-Gal, l-Glc, and Ara at different ratios of 7.3:2.7:1 and 7.6:3.1:1. In addition, the main linkage types of EAP20-1 and EAP20-2 were ß-1,4-Gal, ß-1,6-Gal and α-1,4,6-Glc according to methylation analyses. EAP20-1 and EAP20-2 exhibited significant inhibitory effect on the complement activation through both classical and alternative pathways and with no influence on the coagulation system. Preliminary mechanism study indicated that both EAP20-1 and EAP20-2 inhibited the activation of the complement system by interacting with C1q, C1r, C1s, C2, C4, C5, C7, and C9 components.
[Mh] Termos MeSH primário: Ativação do Complemento/efeitos dos fármacos
Proteínas do Sistema Complemento/imunologia
Eclipta/química
Polissacarídeos/química
Polissacarídeos/farmacologia
[Mh] Termos MeSH secundário: Animais
Coagulação Sanguínea/efeitos dos fármacos
Cromatografia em Gel
Polissacarídeos/isolamento & purificação
Ovinos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polysaccharides); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE


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[PMID]:28926521
[Au] Autor:Mühlbacher J; Jilma B; Wahrmann M; Bartko J; Eskandary F; Schörgenhofer C; Schwameis M; Parry GC; Gilbert JC; Panicker S; Böhmig GA
[Ad] Endereço:1 Department of Surgery, Medical University Vienna, Vienna, Austria. 2 Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria. 3 Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria. 4 True North Therapeutics, Inc., South San Francisco, CA.
[Ti] Título:Blockade of HLA Antibody-Triggered Classical Complement Activation in Sera From Subjects Dosed With the Anti-C1s Monoclonal Antibody TNT009-Results from a Randomized First-in-Human Phase 1 Trial.
[So] Source:Transplantation;101(10):2410-2418, 2017 Oct.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Complement may play a key role in antibody-mediated rejection. A promising therapeutic approach may be classical pathway (CP) inhibition at the level of early component C1. METHODS: In this first-in-human, double-blind, randomized placebo-controlled phase 1 trial, we evaluated the safety and complement inhibitory effect of TNT009, a humanized monoclonal anti-C1s antibody. Sixty-four adult healthy volunteers received either single (n = 48; 7 consecutive cohorts, 0.3-100 mg/kg) or 4 weekly infusions (n = 16; 2 consecutive cohorts, 30 and 60 mg/kg per infusion) of TNT009 or placebo. To assess the effect of treatment on complement activity, sera from dosed subjects were analyzed in a CP activation assay evaluating C3d deposition on HLA-coated microbeads spiked with alloantibodies. RESULTS: Single doses of TNT009 at 3 to 100 mg/kg uniformly and profoundly inhibited HLA antibody-mediated C3d deposition (≥86% after 60 minutes), whereby the duration of CP inhibition (2-14 days) was dose-dependent. Four weekly doses persistently blocked complement for 5 to 6 weeks. Ex vivo serum CP activity was profoundly inhibited when TNT009 concentrations exceeded 20 µg/mL. Infusions were well tolerated without serious or severe adverse events. CONCLUSIONS: Treatment with TNT009 was safe and potently inhibited CP activity. Future studies in patients are required to assess the potential of TNT009 for preventing or treating antibody-mediated rejection.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/administração & dosagem
Ativação do Complemento/efeitos dos fármacos
Complemento C1s/antagonistas & inibidores
Inativadores do Complemento/administração & dosagem
Antígenos HLA/imunologia
[Mh] Termos MeSH secundário: Adulto
Anticorpos Monoclonais Humanizados/efeitos adversos
Anticorpos Monoclonais Humanizados/sangue
Anticorpos Monoclonais Humanizados/uso terapêutico
Complemento C1s/imunologia
Inativadores do Complemento/efeitos adversos
Inativadores do Complemento/sangue
Método Duplo-Cego
Esquema de Medicação
Feminino
Voluntários Saudáveis
Seres Humanos
Infusões Intravenosas
Masculino
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement Inactivating Agents); 0 (HLA Antigens); 0 (TNT009); EC 3.4.21.42 (Complement C1s)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001804


  10 / 9552 MEDLINE  
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[PMID]:28877988
[Au] Autor:Geha M; Tsokos MG; Bosse RE; Sannikova T; Iwakura Y; Dalle Lucca JJ; De Waal Malefyt R; Tsokos GC
[Ad] Endereço:Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
[Ti] Título:IL-17A Produced by Innate Lymphoid Cells Is Essential for Intestinal Ischemia-Reperfusion Injury.
[So] Source:J Immunol;199(8):2921-2929, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ischemia-reperfusion (IR) injury to the small intestine following clamping of the superior mesenteric artery results in an intense local inflammatory response that is characterized by villous damage and neutrophil infiltration. IL-17A, a cytokine produced by a variety of cells in response to inflammatory cytokines released following tissue injury, has been implicated in IR injury. Using , , and mice and administration of anti-IL-17A and anti-IL-23 neutralizing Abs to wild-type mice, we demonstrate that intestinal IR injury depends on IL-17A and that IL-17A is downstream of the binding of autoantibody to ischemia-conditioned tissues and subsequent complement activation. Using bone marrow chimeras, we demonstrate that the IL-17A required for intestinal IR injury is derived from hematopoietic cells. Finally, by transferring autoantibody-rich sera into and mice, we demonstrate that innate lymphoid cells are the main producers of IL-17A in intestinal IR injury. We propose that local production of IL-17A by innate lymphoid cells is crucial for the development of intestinal IR injury and may provide a therapeutic target for clinical exploitation.
[Mh] Termos MeSH primário: Interleucina-17/metabolismo
Intestino Delgado/imunologia
Intestino Delgado/patologia
Linfócitos/imunologia
Traumatismo por Reperfusão/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Bloqueadores/administração & dosagem
Autoanticorpos/metabolismo
Células Cultivadas
Ativação do Complemento
Proteínas de Ligação a DNA/genética
Modelos Animais de Doenças
Seres Humanos
Imunidade Inata
Interleucina-17/genética
Artéria Mesentérica Superior/cirurgia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Infiltração de Neutrófilos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética
Receptores de Interleucina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Blocking); 0 (Autoantibodies); 0 (DNA-Binding Proteins); 0 (Interleukin-17); 0 (Nuclear Receptor Subfamily 1, Group F, Member 3); 0 (Rag2 protein, mouse); 0 (Receptors, Interleukin); 0 (Rorc protein, mouse); 0 (interleukin-23 receptor, mouse)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700655



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