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dc.contributor.advisorEgan, Laurence
dc.contributor.advisorGriffin, Matthew
dc.contributor.authorSlevin, Stephanie
dc.description.abstractMonocytes, recently classified as CD14++CD16- (classical), CD14++CD16+ (intermediate) and CD14dimCD16++ (non-classical) are considered to play a role in the pathogenesis of inflammatory bowel diseases (IBD). Anti-tumor necrosis factor (TNF)-α monoclonal antibodies (mAb) such as infliximab (IFX) dampen inflammation in diseases such as IBD and may in part exert their therapeutic effects via actions on cells that synthesize TNFα such as monocytes. Although clinically effective in many patients, anti-TNFα mAb do not work in some, and lose efficacy in others. A more detailed understanding of the actions of IFX on blood monocytes may provide important insights into the mechanism of action of anti-TNFα mAb and mechanisms of drug resistance. We therefore studied the acute effects of the anti-TNFα mAb IFX on blood monocytes and other mononuclear cells in a cohort of IBD patients. Multi-colour flow cytometry was used to analyse freshly isolated peripheral blood mononuclear cells (PBMCs) from Healthy Controls (HC), Crohn’s Disease (CD) and Ulcerative colitis (UC) patients not receiving IFX and CD and UC patients before (trough) and immediately after (peak) IFX infusion. An array of cytokines and chemokines produced by stimulated PBMCs was assessed at trough and peak IFX drug levels. Monocyte apoptosis (cleaved caspase-3) and lipopolysaccharide (LPS) stimulated TNFα and interleukin (IL)-12 production by intracellular staining of the trough and peak IFX samples were also examined. Compared with the age matched HC group, CD and UC patients had a more pro-inflammatory monocyte and lymphocyte phenotype. CD patients had increased numbers of intermediate monocytes and elevated expression of the inflammatory markers CD86 and CD163. The UC patients had increased total monocyte and granulocyte numbers as well as an expansion of the CD4+ T cells and the CD19+ B cells. IFX caused a prompt reduction in all monocyte subsets in both the CD and UC groups. The CD4+ and CD8+ T cells were significantly reduced in CD patients only. Expression levels of the inflammatory surface markers were not altered with this drug. Quantification of IFX drug levels in CD patients revealed a negative correlation between total monocyte and classical monocyte numbers with increasing levels of IFX. We could find no evidence of IFX-induction of apoptosis to explain the reduction in the number of the circulating PBMCs. The remaining cells secreted less of certain cytokines and chemokines following in-vitro stimulation. The ex vivo production of TNFα and IL-12 by monocytes following LPS stimulation was blunted in whole blood obtained from patients at the post-IFX dosing timepoint, compared to pre-dose. However, this blunting was not observed when isolated monocytes were stimulated. These results show that IBD is associated with a pro-inflammatory monocyte and lymphocyte phenotype when compared to HC. IFX therapy causes a reduction in the number of these circulating monocytes, lymphocytes and respective subsets. This reduction in cell number is not due to apoptosis. The remaining monocytes are dysfunctional in their ability to produce cytokines when stimulated in a whole blood assay but not when isolated cells were used. This observation suggests that ‘reverse signalling’ seems to require the cells to be in contact with other cells and when isolated the blunting effect of IFX is diminished. Overall, monocytes seem to be a key therapeutic target of IFX. The monocytopenic and functional inhibitory actions of IFX on those cells may underlie its clinical efficacy. Future work will be needed to establish if resistance to IFX or other anti-TNFα mAb is mediated at the level of those cells.en_IE
dc.subjectInflammatory bowel diseaseen_IE
dc.subjectRegenerative Medicine Institute (REMEDI)en_IE
dc.subjectSchool of Medicineen_IE
dc.titleThe effects of anti-TNFα antibody therapy on peripheral blood mononuclear cells in patients with inflammatory bowel diseaseen_IE
dc.contributor.funderMolecular Medicine Irelanden_IE
dc.local.noteMonocytes seem to be a key therapeutic target of infliximab; an anti-TNFα monoclonal antibody used for the treatment of inflammatory bowel disease patients. The acute monocytopenic and functional inhibitory actions of infliximab on those cells may underlie its clinical efficacy which is currently not fully understood.en_IE

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