Leukocyte adhesion to P-selectin and the inhibitory role of Crizanlizumab in sickle cell disease: A standardized microfluidic assessment.
Adult
Aged
Anemia, Sickle Cell
/ drug therapy
Antibodies, Monoclonal, Humanized
/ pharmacology
Cell Adhesion
/ drug effects
Female
Humans
Lab-On-A-Chip Devices
/ standards
Leukocytes
/ cytology
Male
Microfluidic Analytical Techniques
/ instrumentation
Middle Aged
P-Selectin
/ antagonists & inhibitors
Young Adult
Adhesion
BioChip
Crizanlizumab
Microfluidics
P-selectin
SEG101
Sickle cell disease
Journal
Blood cells, molecules & diseases
ISSN: 1096-0961
Titre abrégé: Blood Cells Mol Dis
Pays: United States
ID NLM: 9509932
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
18
02
2020
accepted:
08
03
2020
pubmed:
26
3
2020
medline:
13
1
2021
entrez:
26
3
2020
Statut:
ppublish
Résumé
Upregulated expression of P-selectin on activated endothelium and platelets significantly contributes to the initiation and progression of vaso-occlusive crises (VOC), a major cause of morbidity in sickle cell disease (SCD). Crizanlizumab (ADAKVEO®), a humanized monoclonal antibody against P-selectin, primarily inhibits the interaction between leukocytes and P-selectin, and has been shown to decrease the frequency of VOCs in clinical trials. However, the lack of reliable in vitro assays that objectively measure leukocyte adhesion to P-selectin remains a critical barrier to evaluating and improving the therapeutic treatment in SCD. Here, we present a standardized microfluidic BioChip whole blood adhesion assay to assess leukocyte adhesion to P-selectin under physiologic flow conditions. Our results demonstrated heterogeneous adhesion by leukocytes to immobilized P-selectin, and dose-dependent inhibition of this adhesion following pre-exposure to Crizanlizumab. Importantly, treatment with Crizanlizumab following adhesion to P-selectin promoted detachment of rolling, but not of firmly adherent leukocytes. Taken together, our results suggest that the microfluidic BioChip system is a promising in vitro assay with which to screen patients, monitor treatment response, and guide current and emerging anti-adhesive therapies in SCD.
Identifiants
pubmed: 32208292
pii: S1079-9796(20)30062-0
doi: 10.1016/j.bcmd.2020.102424
pmc: PMC7246173
mid: NIHMS1578777
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
P-Selectin
0
crizanlizumab
L7451S9126
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
102424Subventions
Organisme : NHLBI NIH HHS
ID : OT2 HL152643
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133574
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134622
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002548
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest YM, UG, EK, JAL, and UAG are inventors of intellectual property (PCT/US2018/022888 filed on March 16, 2018 and provisional patent application 62/928,109 filed on November 1, 2019) on the microfluidic BioChip technology presented in this manuscript. Competing interests of Case Western Reserve University employees are overseen and managed by the Conflict of Interests Committee according to a Conflict of Interest Management Plan.
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