Ulcerative colitis (UC) belongs to the chronic inflammatory bowel diseases of unknown etiology. A clinical study has shown reduced serum IgE levels and reduced numbers of airway eosinophils in response to treatment with oxelumab however, no effect was observed on allergen-induced airway responses ( Gauvreau et al., 2014). Therefore, agonistic antibodies of OX40 are in development to break tolerance in cancer ( Aspeslagh et al., 2016), whereas neutralizing OX40L antibodies (oxelumab) have been developed for treatment of chronic inflammatory diseases, such as asthma. However, the fact that OX40 signaling is independent of TCR co-stimulation by CD28 has led to increasing interest in the capacity of OX40 to break tolerance indeed, it has been shown that signaling through OX40 breaks peripheral T cell tolerance ( Bansal-Pakala et al., 2001). Hence, it has been suggested that close proximity of T cell receptor (TCR)/CD28 and OX40 signalosomes facilitate co-signaling of both pathways. OX40-triggered responses control longevity, late proliferation and activation states ( Gramaglia et al., 2000 Rogers et al., 2001 Soroosh et al., 2006) and require prior antigen recognition ( So et al., 2011). TNF receptor adaptor factors (TRAFs) mediate the interaction with the PI3K/Akt and NFκB pathway, ultimately leading to proliferation, survival and cytokine expression ( So and Croft, 2013). Upon OX40L and OX40 ligation, OX40 oligomerizes and forms signalosomes in membrane lipid microdomains ( So et al., 2011). Its cognate ligand OX40L (CD252 also known as TNFSF4) is expressed on antigen-presenting, endothelial and mast cells ( Linton et al., 2003 Jenkins et al., 2007 Kashiwakura et al., 2004 Imura et al., 1996). Expression of OX40 is induced in T cells in response to antigen recognition and other pro-inflammatory factors and is thought to augment antigen-initiated signaling to promote proliferation, differentiation and survival of effector and memory CD4 + and CD8 + T cells (for review, see Webb et al., 2016). OX40 (CD134 also known as TNFRSF4) belongs to the family of tumor necrosis factor (TNF) receptors (TNFRs). 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. 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. 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. The clinical, colon and histological scores and the serum concentrations of IL-6, IL-1β and glutamic acid were assessed. 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. CD14 + OX40L + monocytes were correlated significantly with T helper 1 and 2 cells. non-UC: n=5, 30.7☓4.92 P=0.02), whereas no significant difference was detected for CD4 + OX40 +. A significant difference was observed between the groups for CD14 + OX40L + (UC: n=11, 85.44☒1.17, mean±s.d. 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. 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.
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