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[PMID]:29208248
[Au] Autor:Sanghera P; Ghanta M; Ozay F; Ariyamuthu VK; Tanriover B
[Ad] Endereço:Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas.
[Ti] Título:Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options.
[So] Source:Am J Med Sci;354(6):533-538, 2017 12.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Atypical hemolytic uremic syndrome and C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) are characterized as inappropriate activation of the alternative complement pathway. Genetic mutations affecting the alternative complement pathway regulating proteins (complement factor H, I, membrane cofactor protein and complement factor H-related proteins) and triggers (such as infection, surgery, pregnancy and autoimmune disease flares) result in the clinical manifestation of these diseases. A decade ago, prognosis of these disease states was quite poor, with most patients developing end-stage renal disease. Furthermore, renal transplantation in these conditions was associated with poor outcomes due to graft loss to recurrent disease. Recent advances in targeted complement inhibitor therapy resulted in significant improvement in disease remission, renal recovery, health-related quality of life and allograft survival.
[Mh] Termos MeSH primário: Via Alternativa do Complemento/fisiologia
Nefropatias/etiologia
[Mh] Termos MeSH secundário: Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/etiologia
Inativadores do Complemento/uso terapêutico
Via Alternativa do Complemento/efeitos dos fármacos
Glomerulonefrite/tratamento farmacológico
Glomerulonefrite/etiologia
Glomerulonefrite Membranoproliferativa/tratamento farmacológico
Glomerulonefrite Membranoproliferativa/etiologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Complement Inactivating Agents)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


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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]: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


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[PMID]:28832655
[Au] Autor:Danobeitia JS; Ziemelis M; Ma X; Zitur LJ; Zens T; Chlebeck PJ; Van Amersfoort ES; Fernandez LA
[Ad] Endereço:Department of Surgery, Division of Transplantation, University of Wisconsin-Madison, Madison, WI, United States of America.
[Ti] Título:Complement inhibition attenuates acute kidney injury after ischemia-reperfusion and limits progression to renal fibrosis in mice.
[So] Source:PLoS One;12(8):e0183701, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system is an essential component of innate immunity and plays a major role in the pathogenesis of ischemia-reperfusion injury (IRI). In this study, we investigated the impact of human C1-inhibitor (C1INH) on the early inflammatory response to IRI and the subsequent progression to fibrosis in mice. We evaluated structural damage, renal function, acute inflammatory response, progression to fibrosis and overall survival at 90-days post-injury. Animals receiving C1INH prior to reperfusion had a significant improvement in survival rate along with superior renal function when compared to vehicle (PBS) treated counterparts. Pre-treatment with C1INH also prevented acute IL-6, CXCL1 and MCP-1 up-regulation, C5a release, C3b deposition and infiltration by neutrophils and macrophages into renal tissue. This anti-inflammatory effect correlated with a significant reduction in the expression of markers of fibrosis alpha smooth muscle actin, desmin and picrosirius red at 30 and 90 days post-IRI and reduced renal levels of TGF-ß1 when compared to untreated controls. Our findings indicate that intravenous delivery of C1INH prior to ischemic injury protects kidneys from inflammatory injury and subsequent progression to fibrosis. We conclude that early complement blockade in the context of IRI constitutes an effective strategy in the prevention of fibrosis after ischemic acute kidney injury.
[Mh] Termos MeSH primário: Lesão Renal Aguda/prevenção & controle
Complemento C1/antagonistas & inibidores
Inativadores do Complemento/farmacologia
Nefropatias/patologia
Traumatismo por Reperfusão/complicações
[Mh] Termos MeSH secundário: Lesão Renal Aguda/etiologia
Animais
Complemento C1/fisiologia
Modelos Animais de Doenças
Progressão da Doença
Fibrose
Masculino
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C1); 0 (Complement Inactivating Agents)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183701


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[PMID]:28757372
[Au] Autor:DiScipio RG; Schraufstatter IU
[Ad] Endereço:Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92122, United States. Electronic address: rdiscipio@ca.tpims.org.
[Ti] Título:Magnetic bead based assays for complement component C5.
[So] Source:J Immunol Methods;450:50-57, 2017 Nov.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Two novel magnetic agarose bead based assays have been developed to measure complement component C5 interaction with C3b and the Factor I Modules (FIMs) of C7. One innovation was to couple C3b onto the magnetic agarose bead using the alternative pathway C3 convertase, which resulted in a linkage of the ligand by a covalent ester bond. A second innovation was to employ nickel ion charged N,N,N'-tris(carboxymethyl)ethylene-diamine-magnetic agarose to capture recombinantly prepared C7 FIMs that were expressed with an oligo-histidine linker followed by an acidic domain that provided a spacer enabling the C7 modules exposure to C5. Detection was brought about by peroxidase coupled to C5. Both assays exhibited adequate statistics suitable for screening. As examples of the utility of these new methods, we chose to examine influence of natural products on C5 interaction. Fucoidan and ß-glucans were observed to inhibit C3b-C5 interaction, and dextran sulfate was similarly active; however, rosmarinic acid had no measurable effect. In contrast only ß-glucans from two species of macrofungi were able to interfere with interaction of C5 with the FIMs of C7.
[Mh] Termos MeSH primário: Ativação do Complemento
Complemento C3b/imunologia
Complemento C5/imunologia
Complemento C7/imunologia
Técnicas Imunológicas
Magnetismo
[Mh] Termos MeSH secundário: Ativação do Complemento/efeitos dos fármacos
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/metabolismo
Complemento C5/metabolismo
Complemento C7/metabolismo
Ensaio de Atividade Hemolítica de Complemento
Inativadores do Complemento/farmacologia
Sulfato de Dextrana/farmacologia
Hemólise
Seres Humanos
Ferro/química
Polissacarídeos/farmacologia
Ligação Proteica
Sefarose/química
beta-Glucanas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C5); 0 (Complement C7); 0 (Complement Inactivating Agents); 0 (Polysaccharides); 0 (beta-Glucans); 80295-43-8 (Complement C3b); 9012-36-6 (Sepharose); 9042-14-2 (Dextran Sulfate); 9072-19-9 (fucoidan); E1UOL152H7 (Iron); EC 3.4.21.- (Complement C3-C5 Convertases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28732131
[Au] Autor:Thurman JM; Frazer-Abel A; Holers VM
[Ad] Endereço:University of Colorado Denver, Aurora.
[Ti] Título:The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases.
[So] Source:Arthritis Rheumatol;69(11):2102-2113, 2017 Nov.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway-modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement-dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.
[Mh] Termos MeSH primário: Doenças Autoimunes/tratamento farmacológico
Inativadores do Complemento/uso terapêutico
Doenças Reumáticas/tratamento farmacológico
[Mh] Termos MeSH secundário: Doenças Autoimunes/imunologia
Via Alternativa do Complemento/imunologia
Via Clássica do Complemento/imunologia
Lectina de Ligação a Manose da Via do Complemento/imunologia
Proteínas do Sistema Complemento/imunologia
Seres Humanos
Lúpus Eritematoso Sistêmico/tratamento farmacológico
Lúpus Eritematoso Sistêmico/imunologia
Terapia de Alvo Molecular
Doenças Reumáticas/imunologia
Microangiopatias Trombóticas/tratamento farmacológico
Microangiopatias Trombóticas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Complement Inactivating Agents); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1002/art.40219


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[PMID]:28657829
[Au] Autor:Ozen A; Comrie WA; Ardy RC; Domínguez Conde C; Dalgic B; Beser ÖF; Morawski AR; Karakoc-Aydiner E; Tutar E; Baris S; Ozcay F; Serwas NK; Zhang Y; Matthews HF; Pittaluga S; Folio LR; Unlusoy Aksu A; McElwee JJ; Krolo A; Kiykim A; Baris Z; Gulsan M; Ogulur I; Snapper SB; Houwen RHJ; Leavis HL; Ertem D; Kain R; Sari S; Erkan T; Su HC; Boztug K; Lenardo MJ
[Ad] Endereço:From the Section of Molecular Development of the Immune System, Laboratory of Immunology (A.O., W.A.C., A.R.M., H.F.M., M.J.L.), the Clinical Genomics Program (A.O., W.A.C., A.R.M., Y.Z., H.F.M., H.C.S., M.J.L.), and the Human Immunological Diseases Section, Laboratory of Host Defenses (Y.Z., H.C.S.
[Ti] Título:CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.
[So] Source:N Engl J Med;377(1):52-61, 2017 07 06.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
[Mh] Termos MeSH primário: Antígenos CD55/genética
Ativação do Complemento/genética
Proteínas do Sistema Complemento/metabolismo
Mutação
Enteropatias Perdedoras de Proteínas/genética
Trombose/genética
[Mh] Termos MeSH secundário: Antígenos CD55/sangue
Criança
Pré-Escolar
Ativação do Complemento/efeitos dos fármacos
Inativadores do Complemento/farmacologia
Feminino
Homozigoto
Seres Humanos
Imunoglobulina A/sangue
Lactente
Intestino Delgado/patologia
Masculino
Linhagem
Enteropatias Perdedoras de Proteínas/complicações
Estatísticas não Paramétricas
Síndrome
Linfócitos T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD55 Antigens); 0 (Complement Inactivating Agents); 0 (Immunoglobulin A); 9007-36-7 (Complement System Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1615887


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[PMID]:28640789
[Au] Autor:Valenzuela NM; Thomas KA; Mulder A; Parry GC; Panicker S; Reed EF
[Ad] Endereço:1 UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA.2 Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.3 True North Therapeutics Inc., South San Francisco, CA.
[Ti] Título:Complement-Mediated Enhancement of Monocyte Adhesion to Endothelial Cells by HLA Antibodies, and Blockade by a Specific Inhibitor of the Classical Complement Cascade, TNT003.
[So] Source:Transplantation;101(7):1559-1572, 2017 Jul.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling. METHODS: Primary human aortic endothelial cells (HAEC) were stimulated with HLA class I antibodies in the presence of intact human serum complement. C3a and C5a generation, endothelial P-selectin expression, and adhesion of human primary and immortalized monocytes (Mono Mac 6) were measured. Alternatively, HAEC or monocytes were directly stimulated with purified C3a or C5a. Classical complement activation was inhibited by pretreatment of complement with an anti-C1s antibody (TNT003). RESULTS: Treatment of HAEC with HLA antibody and human complement increased the formation of C3a and C5a. Monocyte recruitment by human HLA antibodies was enhanced in the presence of intact human serum complement or purified C3a or C5a. Specific inhibition of the classical complement pathway using TNT003 or C1q-depleted serum significantly reduced adhesion of monocytes in the presence of human complement. CONCLUSIONS: Despite persistent endothelial viability in the presence of HLA antibodies and complement, upstream complement anaphylatoxin production exacerbates endothelial exocytosis and leukocyte recruitment. Upstream inhibition of classical complement may be therapeutic to dampen mononuclear cell recruitment and endothelial activation characteristic of microvascular inflammation during AMR.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Adesão Celular/efeitos dos fármacos
Inativadores do Complemento/farmacologia
Via Clássica do Complemento/efeitos dos fármacos
Células Endoteliais/efeitos dos fármacos
Antígenos HLA-A/imunologia
Imunossupressores/farmacologia
Monócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células Cultivadas
Técnicas de Cocultura
Complemento C3a/farmacologia
Complemento C5a/farmacologia
Relação Dose-Resposta a Droga
Células Endoteliais/imunologia
Células Endoteliais/metabolismo
Exocitose/efeitos dos fármacos
Antígenos HLA-A/metabolismo
Seres Humanos
Antígeno de Macrófago 1/imunologia
Antígeno de Macrófago 1/metabolismo
Monócitos/imunologia
Monócitos/metabolismo
Selectina-P/imunologia
Selectina-P/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Complement Inactivating Agents); 0 (HLA-A Antigens); 0 (Immunosuppressive Agents); 0 (Macrophage-1 Antigen); 0 (P-Selectin); 0 (SELP protein, human); 0 (TNT003); 80295-42-7 (Complement C3a); 80295-54-1 (Complement C5a)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001486


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[PMID]:28622911
[Au] Autor:Tabib A; Karbian N; Mevorach D
[Ad] Endereço:Rheumatology Research Center and Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
[Ti] Título:Demyelination, strokes, and eculizumab: Lessons from the congenital CD59 gene mutations.
[So] Source:Mol Immunol;89:69-72, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Neurological symptoms of patients with p.Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barré syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. We review the possible thrombophilic profile associated with the mutations. In these patients, excessive intravascular hemolysis saturates scavenger mechanisms resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide to form nitrate and methemoglobin, leading to arterial thrombosis. CD59 loss of function is also one of the major thrombophilic mechanisms in patients with paroxysmal nocturnal hemoglobinuria. We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous-, viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Antígenos CD59/genética
Doenças Desmielinizantes/tratamento farmacológico
Mutação
Acidente Vascular Cerebral/tratamento farmacológico
[Mh] Termos MeSH secundário: Ativação do Complemento/efeitos dos fármacos
Inativadores do Complemento/uso terapêutico
Doenças Desmielinizantes/genética
Seres Humanos
Acidente Vascular Cerebral/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (CD59 Antigens); 0 (Complement Inactivating Agents); 101754-01-2 (CD59 protein, human); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


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[PMID]:28610663
[Au] Autor:Nilsson PH; Thomas AM; Bergseth G; Gustavsen A; Volokhina EB; van den Heuvel LP; Barratt-Due A; Mollnes TE
[Ad] Endereço:Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
[Ti] Título:Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses.
[So] Source:Mol Immunol;89:111-114, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/efeitos dos fármacos
Complemento C5/imunologia
Complemento C5a/imunologia
Complemento C5b/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/metabolismo
Síndrome Hemolítico-Urêmica Atípica/sangue
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/imunologia
Cromatografia em Gel
Ativação do Complemento/imunologia
Complemento C5/metabolismo
Complemento C5a/metabolismo
Complemento C5b/metabolismo
Inativadores do Complemento/metabolismo
Inativadores do Complemento/uso terapêutico
Ensaio de Imunoadsorção Enzimática
Epitopos/imunologia
Epitopos/metabolismo
Hemoglobinúria Paroxística/sangue
Hemoglobinúria Paroxística/tratamento farmacológico
Hemoglobinúria Paroxística/imunologia
Seres Humanos
Concentração de Íons de Hidrogênio
Imunoglobulina G/sangue
Imunoglobulina G/imunologia
Avaliação de Resultados (Cuidados de Saúde)
Ligação Proteica/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 0 (Complement Inactivating Agents); 0 (Epitopes); 0 (Immunoglobulin G); 80295-54-1 (Complement C5a); 80295-55-2 (Complement C5b); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE



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