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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.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2021 Jan 01; Vol. 14 (1). Date of Electronic Publication: 2021 Jan 21. - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: Competing interests The authors declare no competing or financial interests.<br /> (© 2021. Published by The Company of Biologists Ltd.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
Antigens, CD metabolism
Antigens, Differentiation, T-Lymphocyte metabolism
CD4-Positive T-Lymphocytes cytology
Colitis, Ulcerative physiopathology
Disease Models, Animal
Female
Humans
Interleukin Receptor Common gamma Subunit metabolism
Lectins, C-Type metabolism
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
OX40 Ligand metabolism
Principal Component Analysis
Receptors, OX40 metabolism
Treatment Outcome
Young Adult
Adalimumab pharmacology
Antibodies, Monoclonal chemistry
Colitis, Ulcerative genetics
Colitis, Ulcerative metabolism
Leukocytes, Mononuclear cytology
OX40 Ligand chemistry
Receptors, OX40 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 33293281
- Full Text :
- https://doi.org/10.1242/dmm.046995