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Suely Meireles Rezendehttp://lattes.cnpq.br/1084050536456702Daniel Gonçalves ChavesJordana Grazziela Alves Coelho dos ReisClara Guerra Duartehttp://lattes.cnpq.br/9812601835461662Larissa Maira Moura de Oliveira2021-03-17T19:44:11Z2021-03-17T19:44:11Z2019-08-01http://hdl.handle.net/1843/35205A hemofilia A (HA) é um distúrbio de sangramento hereditário causado por deficiência de fator (F) VIII. Seu tratamento baseia-se na reposição de FVIII deficiente, tanto profilaticamente quanto sob demanda. Uma das principais complicações da HA é o desenvolvimento de aloanticorpos que inibem a atividade do FVIII (inibidores). Estudos recentes sugerem que o tratamento com infusões repetidas de concentrado de FVIII pode alterar a resposta imune e, portanto, contribui para o desenvolvimento de inibidores. O objetivo deste estudo foi investigar o efeito das infusões de concentrado de FVIII sobre biomarcadores imunológicos de pacientes com HA congênita (PHA). A maioria (80,3%) dos PHA foram incluídos ao diagnóstico e antes de qualquer infusão de FVIII (PUPs; da sigla em inglês, previously untreated patients). Variáveis sociodemográficas, clínicas e laboratoriais foram coletadas. Amostras de plasma foram coletadas na inclusão (T0) e a cada 5-10 dias de exposição (DE) ao FVIII até pelo menos 75 DE (T1/INB-) ou desenvolvimento de inibidor (T1/INB+). Os anticorpos anti-FVIII (IgM, IgG1, IgG3 e IgG4) foram testados por ELISA, bem como um painel de quimiocinas (CCL2, CCL5, CXCL8, CXCL9 e CXCL10) e citocinas (IL-2, IL -4, IL-6, IL-10, IFN-, TNF e IL-17A). Análise estatística descritiva das variáveis e correlação de Spearman entre os biomarcadores foram realizadas. Um total de 71 pacientes com HA grave (FVIII <1%; n=69) e moderadamente grave (FVIII 1%-2%; n=2) foram incluídos. A mediana de idade foi 10 meses (intervalo interquartil [IQR], 6,0-14,0). Em T0, não houve diferença no perfil de citocinas e quimiocinas entre INB- e INB+. Os níveis de CCL2, CXCL9 e CXCL10 foram significativamente menores (p=0,02, p=0,0001 e p=0,02, respectivamente) no grupo INB+ quando comparado com o INB- no estrato 1-20 DE. Os níveis de IgG4 anti-FVIII no grupo INB+ foram significativamente maiores nos estratos 1-20 DE (p=0,001) e 21-75 DE (p=0,01) quando comparados com T0. IgG4 anti-FVIII no grupo INB+ foi significativamente maior no estrato 1-20 DE (p=0,01) quando comparado com o INB-. IgG1 não mostrou diferença significativa entre os dois grupos nem entre os diferentes estratos, mas houve uma tendência de aumento dos níveis no grupo INB+ no estrato 1-20 DE (p=0,08). Concluímos que a infusão de FVIII associou-se a níveis aumentados de citocinas e quimiocinas pró-inflamatórias e aumento dos níveis de IgG1 e IgG4 anti-FVIII em pacientes INB+. Estes resultados sugerem que o FVIII atua modulando seletivamente o sistema imunológico. As quimiocinas (CCL2, CXCL9 e CXCL10) são os elementos-chave que diferenciam os grupos INB- e INB+ durante as primeiras exposições ao FVIII.Hemophilia A (HA) is an inherited bleeding disorder caused by factor (F)VIII deficiency. Its treatment is based on the replacement of deficient FVIII either prophylactically or on demand. One of the major complications of HA is the development of alloantibodies that inhibit FVIII activity (inhibitors). Recent studies suggest that treatment with repeated infusions of FVIII concentrate may alter the immune response and, therefore, contributes to inhibitor development. The objective of this study was to investigate the effect of infusions of FVIII concentrate on immunological biomarkers of patients with congenital HA (PHA). Most (80.3%) PHA were included at diagnosis and before any FVIII infusion (PUPS; previously untreated patients). Socio-demographic, clinical and laboratory variables were collected. Plasma samples were collected at enrollment (T0) and every 5-10 exposure days (ED) to FVIII until at least 75 ED (T1/INB-) or inhibitor development (T1/INB+). Anti-FVIII antibodies (IgM, IgG1, IgG3 and IgG4) were tested by ELISA as well as a panel of chemokines (CCL2, CCL5, CXCL8, CXCL9 and CXCL10) and cytokines (IL-2, IL-4, IL-6, IL-10, INF-, TNF and IL-17A). Descriptive statistical analysis of variables and Spearman correlation between biomarkers were performed. A total of 71 patients with severe (FVIII <1%; n=69) and moderately severe (FVIII 1%-2%; n=2) HA were included. The median age was 10 months (interquartile range [IQR], 6.0-14.0). At T0, there was no difference in the cytokine and chemokine profile between INB- and INB+. The levels of CCL2, CXCL9 and CXCL10 were significantly lower (p=0.02, p=0.0001 and p=0.02, respectively) in the INB+ group when compared with the INB- in the 1-20 ED stratum. Anti-FVIII IgG4 levels in the INB+ group were significantly higher in the strata 1-20 ED (p=0.001) and 21-75 ED (p=0.01) when compared with T0. Anti-FVIII IgG4 in the INB+ group was significantly higher in the 1-20 ED stratum (p=0.01) when compared with INB-. IgG1 showed no significant difference between the two groups nor between the different strata, but there was a trend of increased levels in the INB+ group in the 1-20 DE stratum (p=0.08). We conclude that infusion of FVIII was associated with increased levels of pro-inflammatory cytokines, chemokines, anti-FVIII IgG1 and IgG4 in INB+ patients. These results suggest that FVIII acts by selectively modulating the immune system. Chemokines (CCL2, CXCL9 and CXCL10) are the key elements that differentiate the INB- and INB+ groups during the first exposures to FVIII.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Ciências Aplicadas à Saúde do AdultoUFMGBrasilMEDICINA - FACULDADE DE MEDICINAHemofilia AFator VIII/antagonistas & inibidoresImunidade nas MucosasBiomarcadoresHemofilia AFator VIIIinibidoresresposta imunológicabiomarcadores imunológicosAvaliação do efeito das infusões de fator VIII sobre biomarcadores imunológicos em crianças com hemofilia Ainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALDisertação_Avaliação do efeito das infusões de fator VIII sobre biomarcadores imunológicos em crianças com hemofilia A.pdfDisertação_Avaliação do efeito das infusões de fator VIII sobre biomarcadores imunológicos em crianças com hemofilia A.pdfapplication/pdf7855227https://repositorio.ufmg.br/bitstream/1843/35205/1/Diserta%c3%a7%c3%a3o_Avalia%c3%a7%c3%a3o%20do%20efeito%20das%20infus%c3%b5es%20de%20fator%20VIII%20sobre%20biomarcadores%20imunol%c3%b3gicos%20em%20crian%c3%a7as%20com%20hemofilia%20A.pdf8138cfe812a56b80686ac01d9b25c95eMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82119https://repositorio.ufmg.br/bitstream/1843/35205/2/license.txt34badce4be7e31e3adb4575ae96af679MD521843/352052021-03-17 16:44:11.69oai:repositorio.ufmg.br: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Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2021-03-17T19:44:11Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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