Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients.

BACKGROUND AND AIMS: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-α. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response. METHODS: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column. RESULTS: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome. CONCLUSION: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.

Chemokine receptor expression on monocytes from healthy individuals.

Chronic immune mediated inflammation is characterized by continuous chemokine mediated recruitment and activation of pro-inflammatory cells, monocytes in particular. We believe that an evaluation of the recruitment profile of monocytes during healthy condition is essential for the understanding of cellular response in disease. For this, we have established normal reference values and 95% confidence intervals for receptor expression of 20 chemokine receptors on monocyte subsets; classical (CD14+ CD16−), non-classical (CD14+ CD16+) and HLA-DRhi monocytes from 20 healthy controls using flow cytometry. We demonstrate significant differences in the chemokine receptor expression profiles and high correlation between fraction of cells and level of expression. This is the first global approach to provide a platform for comparable evaluation of cell recruitment during normal and under inflammatory conditions. This will be useful when exploring chemokine­chemokine receptor interactions, inhibition of chemokine signaling and selective removal of migrating cells, which are new treatment strategies in immune mediated diseases.