Head-to-head study of oxelumab and adalimumab in a mouse model of ulcerative colitis based on NOD/Scid IL2Rγnull mice reconstituted with human peripheral blood mononuclear cells.
Adalimumab
/ pharmacology
Adult
Aged
Aged, 80 and over
Animals
Antibodies, Monoclonal
/ chemistry
Antigens, CD
/ metabolism
Antigens, Differentiation, T-Lymphocyte
/ metabolism
CD4-Positive T-Lymphocytes
/ cytology
Colitis, Ulcerative
/ genetics
Disease Models, Animal
Female
Humans
Interleukin Receptor Common gamma Subunit
/ metabolism
Lectins, C-Type
/ metabolism
Leukocytes, Mononuclear
/ cytology
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
OX40 Ligand
/ chemistry
Principal Component Analysis
Receptors, OX40
/ genetics
Treatment Outcome
Young Adult
Anti-CD252 antibodies
Inflammatory bowel disease
NOD/Scid IL2Rγ null
NSG mice
Oxelumab
Ulcerative colitis
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
05
08
2020
accepted:
01
12
2020
pubmed:
10
12
2020
medline:
28
1
2022
entrez:
9
12
2020
Statut:
ppublish
Résumé
This study's aim was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) might lead to patient stratification for treatment with oxelumab. First, immunological profiles of UC patients and non-UC donors were analyzed for CD4+ T cells expressing OX40 (CD134; also known as TNFRSF4) and CD14+ monocytes expressing OX40L (CD252; also known as TNFSF4) by flow cytometric analysis. A significant difference was observed between the groups for CD14+ OX40L+ (UC: n=11, 85.44±21.17, mean±s.d.; non-UC: n=5, 30.7±34.92; P=0.02), whereas no significant difference was detected for CD4+ OX40+. CD14+ OX40L+ monocytes were correlated significantly with T helper 1 and 2 cells. Second, NOD/Scid IL2Rγ null mice were reconstituted with peripheral blood mononuclear cells from UC donors exhibiting elevated levels of OX40L, and the efficacy of oxelumab was compared with that of adalimumab. The clinical, colon and histological scores and the serum concentrations of IL-6, IL-1β and glutamic acid were assessed. Treatment with oxelumab or adalimumab resulted in significantly reduced clinical, colon and histological scores, reduced serum concentrations of IL-6 and reduced frequencies of splenic human effector memory T cells and switched B cells. Comparison of the efficacy of adalimumab and oxelumab by orthogonal partial least squares discrimination analysis revealed that oxelumab was slightly superior to adalimumab; however, elevated serum concentrations of glutamic acid suggested ongoing inflammation. These results suggest that oxelumab addresses the pro-inflammatory arm of inflammation while promoting the remodeling arm and that patients exhibiting elevated levels of OX40L might benefit from treatment with oxelumab.
Identifiants
pubmed: 33293281
pii: dmm.046995
doi: 10.1242/dmm.046995
pmc: PMC7847261
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antigens, CD
0
Antigens, Differentiation, T-Lymphocyte
0
CD69 antigen
0
IL2RG protein, human
0
Il2rg protein, mouse
0
Interleukin Receptor Common gamma Subunit
0
Lectins, C-Type
0
OX40 Ligand
0
Receptors, OX40
0
TNFRSF4 protein, human
0
TNFSF4 protein, human
0
Tnfrsf4 protein, mouse
0
Tnfsf4 protein, mouse
0
Adalimumab
FYS6T7F842
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.