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Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.

ABSTRACT: Sickle cell anemia (SCA) is a hemolytic disease in which vaso-occlusion is an important pathophysiological mechanism. The treatment is based on hydroxyurea (HU), which decreases leukocyte counts and increases fetal hemoglobin synthesis. Different cell types are thought to contribute to vaso-occlusion. Nevertheless, the role of monocytes subsets remains unclear. We investigated frequencies of monocytes subsets in blood and their response to HU therapy, testing their ability to express pro-inflammatory molecules and tissue factor (TF). We identified major changes in monocyte subsets, with classical monocytes (CD14⁺⁺CD16^-) appearing highly frequent in who were not taking HU, whereas those with patrolling phenotype (CD14^dimCD16⁺) were enriched in individuals undergoing therapy. Additionally, HU decreased the production of TNF-?, IL1-?, IL-6, IL-8 as well as TF by the LPS-activated monocytes. Likewise, frequency of TF-expressing monocytes is increased in patients with previous vaso-occlusion. Moreover, activated monocytes expressing TF produced several pro-inflammatory cytokines simultaneously. Such polyfunctional capacity was dramatically dampened by HU therapy. The frequency of classical monocytes subset was positively correlated with percentage cytokine producing cells upon LPS stimulation. These findings suggest that classical monocytes are the subset responsible for multiple pro-inflammatory cytokine production and possibly drive inflammation and vaso-occlusion in SCA which is damped by HU.

SUBMITTER: Guarda CC

PROVIDER: S-EPMC6794261 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.

Guarda Caroline C CC Silveira-Mattos Paulo S M PSM Yahouédéhou Sètondji C M A SCMA Santiago Rayra P RP Aleluia Milena M MM Figueiredo Camylla V B CVB Fiuza Luciana M LM Carvalho Suellen P SP Oliveira Rodrigo M RM Nascimento Valma M L VML Luz Nívea F NF Borges Valéria M VM Andrade Bruno B BB Gonçalves Marilda S MS

Scientific reports 20191015 1

Sickle cell anemia (SCA) is a hemolytic disease in which vaso-occlusion is an important pathophysiological mechanism. The treatment is based on hydroxyurea (HU), which decreases leukocyte counts and increases fetal hemoglobin synthesis. Different cell types are thought to contribute to vaso-occlusion. Nevertheless, the role of monocytes subsets remains unclear. We investigated frequencies of monocytes subsets in blood and their response to HU therapy, testing their ability to express pro-inflamm ...[more]

PMID: 31616024

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Project description:BackgroundHydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.MethodsWe enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell-related events, transfusions, and survival).ResultsA total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).ConclusionsHydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731 .).

Dataset Information

Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.

Publications

Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.

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