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 DOP52 The phenotype of NOD-scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn’s disease or ulcerative colitis reflects the respective disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S089-S092
Author(s):  
A Unterweger ◽  
J Caesar ◽  
P Winkelmann ◽  
A Rüscher ◽  
M Seuß ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
B Cells ◽  
Mouse Models ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Nsg Mice ◽  
Blood Mononuclear Cells

Abstract Background Recently, we have developed a mouse model that relies on NOD-scid IL-2Rγnull (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC, NSG-UC). In this model, symptoms of UC are induced by rectal challenge with ethanol. The objective of the study was to adapt this model to Crohn’s disease and to compare the phenotypes of the NSG-UC and NSG-CD mouse models. Methods NSG mice were reconstituted with PBMC from UC (n = 4) or CD (n = 3) patients. Mice were separated into two groups: unchallenged control and ethanol challenged mice. Readout were clinical-, colon and histological scores, analysis of frequencies of subgroups of human T cells, monocytes and B cells isolated from spleen and colon by flow cytometry, and the expression levels of the inflammatory markers TGFß, CRP, MCP-3, and IL-6 in the colon or serum by Luminex analysis. Results The pathological phenotype was markedly different in NSG-UC mice as compared with NSG-CD mice. Firstly, histological analysis revealed that NSG-UC mice exhibited more of a pro-inflammatory phenotype as indicated by a severe influx of inflammatory cells, oedema, crypt loss, crypt abscesses and epithelial hyperplasia. In contrast, NSG-CD mice displayed crypt loss and goblet cell atrophy and pronounced fibrosis indicating ongoing wound healing processes. These observations were corroborated by frequencies of splenic and colonic leucocytes. Antigen experienced CD4+ T (CD45RO+) cells and switched B cells (CD19+ CD27+ IgD-) were significantly increased in NSG-UC mice, whereas significantly higher levels of experienced CD8+ T cells and M1 (CD64+), M2 (CD163+) CD14+ monocytes and unswitched B cells (CD19+ CD27+ IgD+) indicated a monocyte driven inflammation in NSG-CD mice. This observation was also reflected in the colon of mice. Inflammation in UC was characterised by increased frequencies of neutrophils, activated CD4+ T cells (CD69+) and increased levels of CRP and MCP-3, whereas NSG-CD mice were signified by increased frequencies of M2 and M1 monocytes and of TGFß levels. In contrast to NSG-CD mice, NSG-UC mice also displayed higher serum levels of IL-6. Secondly, the impact of ethanol was more pronounced in the NSG-UC mice. In NSG-CD mice, the challenge did not evoke significant differences as compared with unchallenged control mice. Conclusion The comparison of pathological phenotypes of the NSG-UC and NSG-CD mouse models revealed differences, some of which reflect the respective human disease. The NSG-UC and NSG-CD mouse models may constitute powerful tools to get a better understanding of the different inflammatory processes in UC and CD.

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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