Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Kazuki Horiuchi, Akinori Wada, Shin Nishii, Akinori Mizoguchi, Suguru Ito, Rina Tanemoto, Akira Tomioka, Yoshikiyo Okada, Yoshihiro Akita, Kazuyuki Narimatsu, Masaaki Higashiyama, Shunsuke Komoto, Kengo Tomita, Ryota Hokari

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood, and it is used as induction therapy for IBD. However, its therapeutic mechanism has not been well characterized. Recently, mucosal healing has been emerged as a therapeutic goal for IBD. It has been reported that growth factors play a role in improvement of mucosal repair and regeneration in animal colitis models, and tight junction proteins which impact mucosal permeability play a crucial role in mucosal healing. We investigated that changes in mRNA expression levels of these molecules in colonic mucosa of ulcerative colitis (UC) patients before and after GMA treatment in order to obtain further understanding of GMA therapeutic mechanisms. Methods: Thirty-two active UC patients (Mayo score ≥ 5 and Mayo endoscopic score ≥ 2) were enrolled in this study. All UC patients received 10-11 times of GMA, and colonoscopies were applied before the first GMA (preGMA) and after the last GMA (post-GMA). Assessment of GMA therapeutic efficacy and colonic mucosal healing were determined based on Mayo score. Growth factors such as EGF and HGF, and tight junction proteins such as occludin and ZO-1 mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. Results: After GMA treatment, 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) showed clinical response and 4 patients (12.5%) showed non-response. All patients of the clinical remission group achieved mucosal healing, whereas none of patients in non-response group achieved mucosal healing. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In both pre-GMA and post-GMA, the clinical remission group showed significantly higher expressions of occludin, ZO-1 and EGF mRNA in mucosal tissue than those of the nonresponse group (P <0.05). Post-GMA, HGF mRNA expression tended to be lower in the remission group than those in non-response group. In the non-response group, levels of occludin and ZO-1 mRNA significantly decreased post-GMA compared to their pre-GMA levels (P <0.05), but they were not decreased in the clinical remission group. In contrast, HGF mRNA level decreased post-GMA compared to its pre-GMA level in the remission group, but it was not decreased in the non-response group. Conclusion: In UC patients who achieved clinical remission by GMA, expressions of EGF and tight junction molecules were higher significantly, and mRNA level of HGF decreased after GMA treatment. These results suggest that these molecules play an important role in mucosal healing, and could be helpful for choosing patients who are respond to GMA before treatment

https://www.gastrojournal.org/article/S0016-5085(21)01910-7/pdf

John K Triantafillidis, Emmanuel Merikas, and Filippos Georgopoulos Drug Des Devel Ther. 2011; 5: 185–210. doi: 10.2147/DDDT.S11290

During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn’s disease and ulcerative colitis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084301/

Shoichi Nishise,Yuji Takeda,Yuko Nishise,Shoichiro Fujishima,Tomohiko Orii,Sayaka Otake,Takeshi Sato,Yu Sasaki,Hiroaki Takeda,Sumio Kawata

Biological Effect of Anaphylatoxin C5a on the Generation of Anti-inflammatory Substances in Leukocyte Adsorption. Therap. Apher. Dial. 2009 13(6), 509–514. doi:10.1111/j.1744-9987.2009.00779.x 

Anaphylatoxins, which are involved in both pro-inflammatory processes and a variety of anti-inflammatory effects, are produced during granulocyte and monocyte adsorptive apheresis. We noticed the anti-inflammatory effects of C5a, the strongest anaphylatoxin, in granulocyte and monocyte adsorptive apheresis. The aim of this study was to investigate the effect of C5a on interleukin-1 receptor antagonist (IL-1ra) and hepatocyte growth factor (HGF) generation in granulocyte and monocyte adsorption. Peripheral blood containing nafamostat mesilate as an endogenous complement activation inhibitor was divided into four groups: (1) no recombinant C5a added, no contact with cellulose acetate (CA) beads (control group); (2) no C5a added, contact with CA beads; (3) C5a added, no contact with CA beads; and (4) C5a added, contact with CA beads. After incubation, IL-1ra and HGF in plasma were measured. IL-1ra was significantly higher in group 3, in which only C5a was added in the absence of CA beads, compared to groups 2 (P < 0.01) and 4 (P < 0.05). HGF was significantly higher only in group 4, in which C5a was added in the presence of CA beads (P < 0.05), but did not increase in the absence of CA beads. C5a can directly induce IL-1ra generation without the granulocyte and monocyte adsorption stimuli to CA beads, but can synergistically induce HGF generation with the adsorption stimuli, indicating C5a has different effects on IL-1ra and HGF generation.

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2009.00779.x

Y. Takeda, N. Shiobara, A. R. Saniabadi, M. Adachi & K. Hiraishi, Inflammation Research volume 53, pages 277–283 (2004)

Objective: Evolving evidence of anti-inflammatory effects is observed in patients with rheumatoid arthritis or ulcerative colitis following periodic adsorptive granulocyte and monocyte (GM) apheresis with a column containing cellulose acetate (CA) beads as apheresis carriers. This study was undertaken to obtain insights into mechanisms of anti-inflammatory actions of adsorptive GM apheresis with CA beads. Methods: In a series of in-vitro experiments, we investigated the effects of plasma proteins and the leucocytes β2 integrin (CD18) on granulocyte adsorption to CA beads. Results: Granulocyte adsorption to CA beads required plasma IgG, the complement C3 and was inhibited by an antibody to leucocytes CD18. Further, hepatocyte growth factor (HGF) and interleukin-1 receptor antagonist (IL-1ra) which have strong anti-inflammatory actions were released by granulocytes that adhered to CA beads. Conclusions: Plasma IgG, C3 derived complement activation fragments and leucocytes CD18 are involved in granulocyte adhesion to CA beads and hence the release of HGF and IL-1ra.

https://link.springer.com/article/10.1007/s00011-004-1253-5