Giorgos Bamias ¹, Evanthia Zampeli ², Eugeni Domènech ³ Expert Rev Gastroenterol Hepatol  2022 Jul 19;1-15. doi: 10.1080/17474124.2022.2100759.

Introduction: Inflammatory bowel disease (IBD) is a chronic immune-mediated disease of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). While any part of the digestive tract can be affected in CD, mucosal inflammation in UC is limited to the colon. Differences and similarities between the two conditions are reflected by their pathophysiology. Areas covered: An overview of immunological aspects, pharmacological management, and biomarkers of IBD is provided. The role of adsorptive granulocyte and monocyte apheresis (GMA) is reviewed including its primary and secondary effects on the immune system, as well as clinical studies in IBD (mainly UC), and potential biomarkers for adsorptive GMA. Expert opinion: In UC, adsorptive GMA with Adacolumn (Adacolumn®, JIMRO Co., Ltd. Takasaki, Gunma, Japan) selectively depletes elevated myeloid lineage leukocytes and has a range of beneficial secondary immune effects. Adsorptive GMA is a safe and effective non-pharmacological treatment option for UC. Pilot studies have reported promising results for adsorptive GMA in combination with biological agents, although larger studies are required. Fecal calprotectin concentrations, neutrophil counts in histological samples and/or the neutrophil/lymphocyte ratio in peripheral blood may prove to be useful biomarkers for predicting GMA effectiveness in the future.

https://pubmed.ncbi.nlm.nih.gov/35833363/

https://www.tandfonline.com/doi/epub/10.1080/17474124.2022.2100759?needAccess=true

Yoshitaka Hara ¹, Yasuyo Shimomura ¹, Tomoyuki Nakamura ¹, Naohide Kuriyama ¹, Chizuru Yamashita ¹, Yu Kato ¹, Taku Miyasho ², Toshikazu Sakai ¹, Shingo Yamada ³, Kazuhiro Moriyama ¹, Osamu Nishida ¹ , Ther Apher Dial 2015 Aug;19(4):308-15.

We have been developing a new blood purification system for regulating excessive immune reactions in severe sepsis and septic shock using a granulocyte adsorbing column (Adacolumn [Ada]), and a cytokine-adsorbing hemofilter (AN69ST hemofilter [AN69]). Fresh porcine blood was circulated for 6 h in five experimental groups including Ada and AN69 to assess the effects of leukocyte adsorption, phagocytic activity and adhesiveness of granulocytes. In the present study, we found that Ada mainly adsorbed granulocytes and monocytes, but not lymphocytes. The phagocytic activity level of granulocytes decreased, and adhesiveness increased, but the number of CD11b-positive cells markedly decreased in the current system. Elevated cytokine levels (IL-1β, IL-8 and IL-10) at the outlet of Ada were significantly lower than at the outlet of AN69 due to cytokine adsorption. Further studies are needed to better understand cellular interactions.

https://pubmed.ncbi.nlm.nih.gov/26386217/

Yuko Iwakami,Atsushi Sakuraba,Toshiro Sato,Yasuhiro Takada,Motoko Izumiya,Hitoshi Ichikawa,Toshifumi Hibi Ther Apher Dial 13, 2 (2009); 138-146

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-γ (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16⁺ monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocytcde antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-γ and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.

https://pubmed.ncbi.nlm.nih.gov/19379153/

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2009.00668.x

Maria T Abreu ¹, Scott Plevy, Bruce E Sands, Robert 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.

https://pubmed.ncbi.nlm.nih.gov/18090155/

Masakazu Takazoe ¹, Torao Tanaka, Kenji Kondo, Toshiki Ichimori, Toshio Shinoda Ther Apher 2002 Aug;6(4):305-11. doi: 10.1046/j.1526-0968.2002.00445.x.

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well elucidated in the recent years. The pharmacologic treatment of IBDs accordingly becomes to focus upon the individual pathologic step (targeting therapy), whereas the therapeutic action is not yet a pinpoint one. It has been known recently that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than the conventional drugs, and they might alter the treatment strategy of IBDs in the near future. The limitation of pharmacologic treatments mainly results from adverse effects of the drugs, i.e. infection susceptibility, oncogenesis, teratogenesis and so forth. The extracorporeal therapy such as leukocytapheresis and photopheresis is reportedly effective for IBDs probably through immunomodulation such as decrease in circulating activated T-lymphocytes and activated granulocytes that play a central role in the pathogenesis of IBD. It can be said that these extracorporeal treatment methods have advantage of rapid action and lack of serious adverse effects to drug therapy.

https://pubmed.ncbi.nlm.nih.gov/12164801/

Nobuhito Kashiwagi ¹, Kazuhito Sugimura, Hirobumi Koiwai, Hironori Yamamoto, Toshikazu Yoshikawa, Abby R Saniabadi, Masakazu Adachi, Takashi Shimoyama

Dig Dis Sci. 2002 Jun;47(6):1334-41. doi: 10.1023/a:1015330816364.

Our aim was to understand the mechanism of immunological changes associated with the use of an adsorptive-type extracorporeal device (Adacolumn) that has been developed for selective adsorption of granulocytes and monocytes/macrophages from peripheral blood of patients with active ulcerative colitis. The column is filled with carriers (G-1 beads) that have a diameter of 2 mm and are made of cellulose diacetate. In peripheral blood treated with the G-1 beads or peripheral blood from patients with active ulcerative colitis following granulocyte and monocyte adsorption apheresis, a significant suppression of proinflammatory cytokines (tissue necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8) production by leukocytes, neutrophil chemotaxis, down-regulation of leukocyte adhesion molecule (L-selectin) and neutrophil adhesion to interleukin-1beta-activated endothelial cells were observed. Furthermore, after granulocyte adsorption therapy, the number of CD10-negative premature granulocytes increased, indicating increased turnover of these cells in the circulation. Our observations suggest that selective granulocyte and monocyte adsorption is associated with modified peripheral blood leukocyte function favorable to patients with ulcerative colitis and possibly other autoimmune disorders which reflect leukocyte hyperactivity.

https://pubmed.ncbi.nlm.nih.gov/12064810/

N Kashiwagi ¹, I Hirata, R Kasukawa

Ther Apher. 1998 May;2(2):134-41. doi: 10.1111/j.1744-9987.1998.tb00091.x.

Rheumatoid arthritis (RA) is an inflammatory condition, the etiology of which is not well understood. Recent reports indicate a major role of granulocytes in the pathogenesis of RA; arthritic joints are infiltrated with phagocytic leukocytes, granulocytes, and monocytes/macrophages, and it is believed that these cells, by releasing degradative proteinases, cytokines, and reactive oxygen species, contribute to joint destruction. Hence, the apheresis of granulocytes and monocytes may benefit patients with RA. Granulocyte and monocyte apheresis was carried out in 143 patients with RA using an apheresis column (G-1) packed with 220 g cellulose acetate beads, which selectively adsorb granulocytes and monocytes. Patients received 1 or 2 apheresis sessions, each of 1 h duration per week over a 4 week period at a flow rate of 30 ml/min. Apheresis significantly reduced swollen and tender joint counts and the duration of morning stiffness, and it increased grip strength, together with suppression of tumor necrosis factor-alpha and interleukin-1beta production by peripheral blood monocytes. It is concluded that this alternative treatment induces a kind of immunomodulation.

https://pubmed.ncbi.nlm.nih.gov/10225715/

N Kashiwagi ¹, I Hirata, R Kasukawa

Ther Apher. 1998 May;2(2):134-41. doi: 10.1111/j.1744-9987.1998.tb00091.x.

Rheumatoid arthritis (RA) is an inflammatory condition, the etiology of which is not well understood. Recent reports indicate a major role of granulocytes in the pathogenesis of RA; arthritic joints are infiltrated with phagocytic leukocytes, granulocytes, and monocytes/macrophages, and it is believed that these cells, by releasing degradative proteinases, cytokines, and reactive oxygen species, contribute to joint destruction. Hence, the apheresis of granulocytes and monocytes may benefit patients with RA. Granulocyte and monocyte apheresis was carried out in 143 patients with RA using an apheresis column (G-1) packed with 220 g cellulose acetate beads, which selectively adsorb granulocytes and monocytes. Patients received 1 or 2 apheresis sessions, each of 1 h duration per week over a 4 week period at a flow rate of 30 ml/min. Apheresis significantly reduced swollen and tender joint counts and the duration of morning stiffness, and it increased grip strength, together with suppression of tumor necrosis factor-alpha and interleukin-1beta production by peripheral blood monocytes. It is concluded that this alternative treatment induces a kind of immunomodulation.

https://pubmed.ncbi.nlm.nih.gov/10225715/

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1744-9987.1998.tb00091.x?sid=nlm%3Apubmed