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

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.

The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease

“…Mice were obtained from Charles River Laboratories and kept under specific pathogen‐free conditions in individually ventilated cages in a facility controlled according to the Federation of Laboratory Animal Science Association guidelines as described previously 25 . Six‐ to eight‐week old NOD.cg‐Prkdc SCID Il2rg tm1Wjl /Szj mice (abbreviated as NOD‐scid IL‐2Rγ null , NSG) were engrafted with 100 µl PBMC cell solution (4 × 10 6 ) into the tail vein on Day 1 as previously described 25 and presensitized by rectal application of 150 µl 10% ethanol on Day 7 using a 1 mm catheter (Henry Schein). The catheter was lubricated with lidocaine 2% gel (AstraZeneca) 25 .…”

“…Six‐ to eight‐week old NOD.cg‐Prkdc SCID Il2rg tm1Wjl /Szj mice (abbreviated as NOD‐scid IL‐2Rγ null , NSG) were engrafted with 100 µl PBMC cell solution (4 × 10 6 ) into the tail vein on Day 1 as previously described 25 and presensitized by rectal application of 150 µl 10% ethanol on Day 7 using a 1 mm catheter (Henry Schein). The catheter was lubricated with lidocaine 2% gel (AstraZeneca) 25 . Rectal application was performed under general anesthesia using 4% isoflurane.…”

“…Sections from distal parts of the colon were fixed in 4% formaldehyde for 24 h, stored in 70% ethanol and embedded in paraffin as described previously 25 . A total of 3 µm sections were cut and stained with haematoxylin and eosin (HE), periodic acid‐Schiff (PAS) and Masson‐Goldner trichrome (MGT, all from Morphisto GmbH).…”

“…The catheter was lubricated with lidocaine 2% gel (AstraZeneca). 25 Rectal application was performed under general anesthesia using 4% isoflurane. Following application mice were kept at an angle of 30° to avoid ethanol dripping.…”

NOD/scid IL‐2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype

“…About 60 ml of peripheral blood in trisodium citrate solution (S‐Monovette, Sarstedt) were collected from the arm vein of UC and CD patients as described previously 20 . The blood was diluted with Hank's balanced salt solution (HBSS, Sigma Aldrich) in a 1:2 ratio.…”