scholarly journals A mouse model for ulcerative colitis based on NOD-scidIL2R γnullmice reconstituted with peripheral blood mononuclear cells from affected individuals

2016 ◽  
Vol 9 (9) ◽  
pp. 985-997 ◽  
Author(s):  
Pia Palamides ◽  
Henrika Jodeleit ◽  
Michael Föhlinger ◽  
Florian Beigel ◽  
Nadja Herbach ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Model ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals The Combination of Patient Profiling and Preclinical Studies in a Mouse Model Based on NOD/Scid IL2Rγ null Mice Reconstituted With Peripheral Blood Mononuclear Cells From Patients With Ulcerative Colitis May Lead to Stratification of Patients for Treatment With Adalimumab

2019 ◽  
Vol 26 (4) ◽  
pp. 557-569
Author(s):  
Henrika Jodeleit ◽  
Janina Caesar ◽  
Christina Villarroel Aguilera ◽  
Sebastian Sterz ◽  
Lesca Holdt ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Model ◽  
Hierarchical Clustering ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Nsg Mice ◽  
Immunological Phenotype ◽  
Blood Mononuclear Cells

Abstract Background To date, responsiveness to tumor necrosis factor alpha inhibitors in ulcerative colitis (UC) patients is not predictable. This is partially due to a lack of understanding of the underlying inflammatory processes. The aim of this study was to identify immunological subgroups of patients with UC and to test responsiveness to adalimumab in these subgroups in the mouse model of ulcerative colitis (UC), which is based on NOD/scid IL-2Rγ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs; NSG-UC). Methods The immunological profiles of 40 UC patients and 16 non-UC donors were determined by flow cytometric analysis of PBMCs in a snapshot and longitudinal study and analyzed by principal component, orthogonal partial least square discrimination (oPLS-DA), and hierarchical clustering analysis. NSG mice were reconstituted 5 times at consecutive time points with PBMCs from a single donor and were analyzed for frequencies of human leukocytes and histological phenotype. The response to adalimumab of 2 identified subgroups was tested in the NSG-UC model. We used the clinical, colon, and histological score, serum levels of glutamic and aspartic acid, and IL-6 and IL-1ß. Response was analyzed by oPLS-DA. Results Analysis revealed a distinction between UC and non-UC donors. Hierarchical clustering identified 2 major subgroups in UC patients. Group I was characterized by TH17 and M1 monocytes, group II by TH2/TH1, and switched B cells. These subgroups reflect the dynamics of inflammation as patients. NSG-UC mice achieved an immunological phenotype reflecting the patient’s immunological phenotype. oPLS-DA revealed that NSG-UC mice reconstituted with PBMCs from group II responded better to adalimumab. Conclusions The combination of profiling and testing of therapeutics in the NSG-UC model may lead to individualized and phase-dependent therapies.

scholarly journals Head to head study of oxelumab and adalimumab in a mouse model of ulcerative colitis based on NOD/Scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells

2020 ◽  
pp. dmm.046995
Author(s):  
Henrika Jodeleit ◽  
Paula Winkelmann ◽  
Janina Caesar ◽  
Sebastian Sterz ◽  
Lesca M. Holdt ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Mouse Model ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Serum Levels ◽  
Peripheral Blood Mononuclear ◽  
Significant Difference ◽  
Blood Mononuclear Cells

The goal of this study was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) may 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) and CD14+ monocytes expressing OX40L (CD252) by flow cytometric analysis. A significant difference was observed between both groups for CD14+ OX40L+ (UC: n=11, 85.44±21.17; mean±sd, non-UC: n=5, 30.7±34.92; p=0.02), no significant difference was detected for CD4+ OX40+. CD14+ OX40L+ monocytes correlated significantly with TH1 and TH2 cells. Secondly, NOD/Scid IL2-Rgamma null mice were reconstituted with peripheral blood mononuclear cells from UC donors exhibiting elevated levels of OX40L, and the efficacy of oxelumab was compared to that of adalimumab. Read out were the clinical, colon, andhistological scores, and serum levels of IL-6, IL-1ß and glutamic acid. Treatment with oxelumab or adalimumab resulted in significantly reduced clinical, colon, and histological scores, reduced serum levels of IL-6 and reduced frequencies of splenic human effector memory T cells and switched B cells. Comparison of efficacy of adalimumab and oxelumab by orthogonal partial least square discrimination analysis revealed that oxelumab was slightly superior to adalimumab, however, elevated serum levels 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 may benefit from treatment with oxelumab. Keywords: Ulcerative colitis, NOD/Scid IL2-Rγnull, NSG, anti-CD252 antibodies, oxelumab, inflammatory bowel disease

scholarly journals Lipopolysaccharide and silica-stimulated mononuclear cell prostaglandin production in ulcerative colitis

2000 ◽  
Vol 9 (3-4) ◽  
pp. 189-191
Author(s):  
Neville A. Punchard ◽  
John Cason ◽  
Jonathan Mullins ◽  
Chaman Chander ◽  
Richard P. H. Thompson
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Mononuclear Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Prostaglandin Production ◽  
Blood Mononuclear Cells

Basal, lipopolysaccharide (LPS) and silica-stimulated prostaglandin (PG) production were compared between peripheral blood mononuclear cells (PBMNC) from UC patients and healthy subjects (HS). Basal and LPS-stimulated PBMNC PGI2, but not PGE2, production was greater in UC. LPS stimulated both PGE2and PGI2by PBMNC from HS and UC patients. Silica stimulated production of both PGs by cells from HS but only PGE2by cells from UC patients. The differences in responses to silica and LPS may result from differences in activation of NFκB or, alternatively, prior sensitisation to one of these agents. That PBMNC PGE2production is not increased in UC, as it is in Crohn’s disease, suggests that there are differences in PBMNC behaviour between these two diseases.

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