Scientific corner

Granulocyte and monocyte adsorptive apheresis induces apoptosis of neutrophils and release of a novel chemoattractant for desensitization of interleukin-8 response

Nobuhito Kashiwagi Fumio Saito Hidetaka Maegawa Kenta Kaneda, Cytokine 2021 Mar;139:155410.

Objective: Apoptotic cells participate in maintenance of homeostasis of the adaptive immune system. Granulocyte/monocyte adsorptive apheresis (GMA) performed with an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects for immune-mediated disorder cases, such as inflammatory bowel disease (IBD) or psoriatic arthritis. Although induction of apoptosis in neutrophils by GMA has been observed, the detailed mechanism remains unclear. Methods: To focus on phagocytosis-induced cell death (PICD) that induces apoptotic neutrophils, a comparative study utilizing a GMA-carrier (leukocyte adsorbing carrier for Adacolumn) and yeast particles was performed with in vitro and in vivo examinations. Results: L-selectin was significantly (P = 0.0133) shed, reactive oxygen species (ROS) production was promoted (P = 0.0019), and apoptosis induction was enhanced (P = 0.0087) by peripheral blood co-cultured with the GMA-carrier or yeast particles as compared to incubated blood alone. Furthermore, degranulation of myeloperoxidase, elastase, and lactoferrin was increased by both treatments, while the highest level of interleukin-1 receptor antagonist release was found with GMA-carrier treatment (P = 0.0087) as compared to the yeast particles. Plasma from blood treated with the GMA-carrier showed chemotactic activity, and suppressed neutrophil migration to IL-8 and LTB4. In vivo results demonstrated that neutrophil chemotaxis to IL-8 was desensitized (P = 0.0078) in rabbits following GMA apheresis, while CXCR1 and CXCR2 expressions in neutrophils were reduced by exposing peripheral blood to the GMA-carrier. Conclusions: GMA may regulate the immune system in patients with an immune-mediated disorder by inducing a biological response of neutrophils with a PICD-like reaction.

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Sa1316 Granulocyte and Monocyte Adsorptive Apheresis (GMA) Might Be Useful for Patients With Ulcerative Colitis by Inhibition of S100A12-S100a12 Correlates With Acute and Chronic Inflammation by Induction of CCL and CXCL Chemokines

Shingo Kato, Kazuhito Kani, Hidehiko Takabayashi, Ryuichi Yamamoto, Koji Yakabi Gastroenterology 2011 140(5) Suppl. S-279–S-280

Backgrounds&Aims; Granulocyte and monocyte adsorptive apheresis (GMA) adsorbs mainly granulocyte and monocytes, as well as Leukocyteapheresis (LMA) filters many cells such as granulocyte, monocytes, lymphocytes and platelets. However, there was no significant difference in clinical effectiveness between GMA and LMA (Eur J Gastroenterol Hepatol 2008;20:629). We hypothesized effectiveness of GMA and LMA might be dependent on depletion of granulocyte and monocytes. S100A12 was reported to be exclusively expressed in neutrophils and up-regulated by TNF α. The aim of this study was to investigate the changes of serum S100 A12 concentration in the GMA treatments and whether S100A12 increases the expression of adhesion molecules, CXCL and CCL chemokines. Methods; 24 patients with ulcerative colitis were treated with GMA. Serum S100A12 was estimated by ELISAmethods.Clinicalactivityindex(CAI)andserumCRPconcentrationwerealsochecked. Immunohistochemical staining of S100A12 and receptor for advanced glication end products (RAGE) were performed in the operated specimens of patients with ulcerative colitis and with colonic carcinoma (control). HUVEC were seeded into 12 well plates and confluent plates were used to experiments. Each experiment was performed in triplicate. HUVEC were treated with human recombinant S100A12 protein. RNA was extracted by RNeasy Mini Kit. 1.5μg RNA was reverse-transcriptated into cDNA. ICAM-1, VCAM-1, IL-8, CCL-2 (MCP1), CCL5 (RANTES), CXCL9 (IP-10) and CXCL10 (Mig) mRNA was quantitated by realtime PCR. Results; S100A12 staining was faintly recognized in the mucosal layer of normal control. S100A12 staining was increased in infiltrating cells in inflamed colon in patients with ulcerative colitis. Strong staining was also recognized in crypt abscess. RAGE staining was also faintly recognized in the epithelial cells in nornmal control. However, RAGE staining was increased in the inflamed epithelial cells. Significantly serum S100A12 concentration was positively correlated with CAI (n=34, p=0.02, rs=0.404). 16 patients were able to estimate S100A12 concentration in the points of pre-and post-GMA treatment. 13 patients wereGMA-respondersand3patientswere nonGMA-responders.SerumS100A12concentration was significantly decreased in GMA responders (pre-vs post-GMA, 1.34±1.08 vs 0.60±0.50, p<0.05). However, Serum S100A12 concentration of non GMA-responders was gradually increased with GMA treatments. ICAM-1, VCAM-1, IL-8, IP-10, Mig, MCP-1 and RANTES mRNA expressions were increased by S100A12 in HUVEC cell lines in time and dose-dependent manners. Conclusion; one of the mechanisms of GMA effect might be correlated with depletion of S100A12 by adsorption of activated neutrophils. S100A12 might aggravate acute and chronic inflammation by up-regulation of adhesion molecules, CXCL and CCL chemokines.

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Immunoregulatory Effects of Adsorptive Granulocyte and Monocyte Apheresis in Patients with Drug Refractory Crohn’s Disease

Kazuko Nagase 1Ken FukunagaShinichiro KashiwamuraTomoaki KonoKoji KamikozuruYoko YokoyamaNobuyuki HidaYoshio OhdaNaohisa TakedaKoji YoshidaMasaki IimuroRisa KikuyamaKyoichi KatoHiroto MiwaTakayuki Matsumoto, Ther Apher Dial. 2011 Aug;15(4):367-73.

In Japan, adsorptive granulocyte/monocyte apheresis (GMA) is an approved treatment option in patients with active Crohn’s disease (CD). However, there is inadequate knowledge regarding the mechanism(s) of therapeutic effects of this non-pharmacologic treatment strategy. Further, recently we have been interested in the regulatory T-cell (Treg) profile which has an essential immunoregulatory function. Thirteen CD patients were treated with a single GMA session. The mean CD activity index (CDAI) and duration of CD were 218.5 and 9.8 years, respectively. Eight healthy volunteers participated as a control group. From CD patients, whole blood was taken immediately before and after the GMA session directly from the GMA column inflow and outflow lines. Broad spectrum serum key cytokines and chemokines were measured by suspension-array and ELISA. At baseline, almost all assayed inflammatory cytokines were significantly elevated in CD patients. Treg-associated cytokines including IL-10 (P < 0.02) and transforming growth factor (TGF)-β1 (P < 0.03), were higher in the GMA column outflow vs. inflow. In contrast, the Th1/Th2 balance, defined as IFN-γ/IL-10 was lower during hemofiltration (P = 0.05), potentially due to an elevated IL-10 (P < 0.02) because an elevation of pro-inflammatory IFN-γ (Th1) was not observed at the GMA column outflow. A single GMA session had a significant impact on the Treg profile. Treg-related cytokines like IL-10 and TGF-β1 in the blood returning to the patients from the GMA column outflow were elevated, while pro-inflammatory cytokines like IFN-γ were not. This action of GMA is potentially very interesting in patients with immune disorders, like CD patients.

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Selective leukocyte apheresis for the treatment of inflammatory bowel disease

Maria T Abreu 1Scott PlevyBruce E SandsRobert Weinstein, J Clin Gastroenterol. Nov-Dec 2007;41(10):874-88.

The etiology of inflammatory bowel disease (IBD) is not completely understood, thus current therapies have been empirical and directed at treating symptoms rather than addressing the cause. In IBD, the overexpression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, leads to a persistent intestinal inflammatory response that damages the intestinal mucosa. Recent advances in pharmacologic therapies that target specific cytokines, chemokines, and adhesion molecules have proved successful in alleviating symptoms for some patients. There are 2 selective adsorption apheresis devices that remove leukocytes from whole blood, which are currently available in Japan and Europe-the Cellsorba leukocytapheresis column and the Adacolumn adsorptive extracorporeal granulocyte/monocyte apheresis device. The purported mechanisms of action of these devices have been extensively reviewed and are believed to exert an immunomodulatory and/or anti-inflammatory effect on patients with systemic inflammatory disease.The clinical trials presented here indicate that selective leukocyte apheresis effectively removes activated granulocytes and monocytes/macrophages from peripheral blood while maintaining an excellent safety profile. Despite these findings, large controlled trials of selective leukocyte apheresis in the treatment of IBD are needed to determine the true efficacy of this approach.

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