Yoko Yokoyama ¹, Ken Fukunaga, Yoshihiro Fukuda, Katsuyuki Tozawa, Koji Kamikozuru, Kunio Ohnishi, Takeshi Kusaka, Tadashi Kosaka, Nobuyuki Hida, Yoshio Ohda, Hiroto Miwa, Takayuki Matsumoto Dig Dis Sci 2007 Oct;52(10):2725-31. doi: 10.1007/s10620-006-9560-z. Epub 2007 Apr 3.

Low-CD25(High+)CD4(+), a subset of regulatory CD25(+)CD4(+) T cells and high-inflammatory CD28(-)CD4(+) T cells can exacerbate ulcerative colitis (UC). This study sought to investigate the frequency of CD25(High+)CD4(+) and CD28(-)CD4(+) T cells in patients with UC and the changes in these cells during Adacolumn granulocyte and monocyte adsorption apheresis (GMA). Subjects were 12 patients with active UC, 11 with quiescent UC, and 14 healthy volunteers (HVs). The mean clinical activity index was 15.7 +/- 2.2 in active UC and 4.5 +/- 1.1 in quiescent UC. Peripheral blood samples were stained with CD4, CD25, and CD28 antibodies for flow cytometry. Patients with active UC received GMA and blood samples were examined before and after the first GMA session. Patients with active UC (P < 0.04) or quiescent UC (P < 0.02) had a higher percentage of CD28(-)D4(+)T cells compared with HVs, while the percentage of CD28(+)CD4(+) T cells was lower in both UC groups compared with HVs (P = 0.03 and P < 0.02). Patients with active UC had a lower percentage of CD25(High+)CD4(+)T cells compared with quiescent UC patients (P < 0.001). A significant increase in CD25(High+)CD4(+) T cells was associated with GMA (P < 0.03). Low CD25(High+)CD4(+) and high CD28(-)CD4(+) are prominent features in UC. The increase in CD25(High+)CD4(+) T cells induced by GMA should contribute to improved immune function. Additional studies are warranted, since a low frequency of CD25(High+)CD4(+) (-) and a high frequency of CD28(-)CD4(+) (-) expressing T cells might be a predictor of clinical response to GMA.

https://pubmed.ncbi.nlm.nih.gov/17404876/

Yuji Naito ¹, Tomohisa Takagi, Toshikazu Yoshikawa

J Gastroenterol  2007 Oct;42(10):787-98. doi: 10.1007/s00535-007-2096-y. Epub 2007 Oct 15.

Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a “molecular fingerprint” of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.

https://pubmed.ncbi.nlm.nih.gov/17940831/

Abbi R.Saniabadi, HiroyukiHanai, KenFukunaga, KojiSawada, ChikakoShima, IngvarBjarnason, RobertLofberg, https://doi.org/10.1016/j.transci.2007.08.003

The inference that granulocytes and monocytes/macrophages (GM) are part of the immunopathogenesis of inflammatory bowel disease (IBD) and hence should be targets of therapy stems from observations of elevated, and activated GM in patients with IBD. The Adacolumn can selectively deplete GM by adsorption (GMA) and in patients with IBD. GMA has been associated with significant clinical efficacy together with sustained suppression of inflammatory cytokine profiles. Additionally, GMA depleted proinflammatory CD14⁺CD16⁺ monocytes and was followed by an increase in CD4⁺ T lymphocytes including the regulatory CD4⁺CD25^high+Foxp3 phenotype. Hence, GMA could be a non-pharmacologic therapy for IBD with potential to spare steroids and other unsafe pharmacologic preparations.

https://www.sciencedirect.com/science/article/abs/pii/S1473050207001164

J. Muñoz, M. Clavo, O. Garcia, D. Reina, A. Vidaller, R. Lafuente & L. I. Massuet

ISBT Science Series (2007) 2, 96–101

There is a strong basis to support the modulators properties of innate immunity of GCAP, although there is a lack of data that explains deeply the interactions between the mechanisms involved. GMA may represent a new therapy that offers not a single pathway effect but a global modulation of the most important pathways involved in innate immune response. Future investigations should elucidate the intimate mechanism of action.

https://www.researchgate.net/publication/239319651_Adsorptive_monocyte_and_granulocyte_apheresis_in_the_chronic_inflammatory_illness_ulcerous_colitis_Crohn’s_disease_rheumatoid_arthritis_and_Behcet_syndrome

Ken Fukunaga, Hiroto Miwa, Takayuki Matsumoto January 2007 Tropical gastroenterology: official journal of the Digestive Diseases Foundation 28(1):11-5

Ulcerative colitis (UC) together with Crohn’s disease (CD) constitute idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but autoimmune-disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocyte removal therapy (ELRT) is the latest adjunct for IBD patient refractory to steroids, and it aims at suppressing immunological response by removing circulating leukocytes, especially granulocytes, from the blood stream. The present paper reviews the latest evidences in order to propose the current status of ELRT in the therapeutic strategy for IBD, especially for UC and CD. Clinical experience so far suggests that ELRT has superior efficiency as a non-pharmacological immuno-modulative therapy for steroid resistant UC patients before submission to colectomy. Moreover, ELRT has been proven to be a safe therapy compared with other current medications for severe UC.

https://www.researchgate.net/publication/5947344_Role_of_leukocytapheresis_in_the_management_of_inflammatory_bowel_disease

Alvaro A Pineda ¹ , Inflamm Bowel Dis. 2006 Jan;12 Suppl 1:S10-4.

Initially used to treat rheumatoid arthritis, nonselective therapeutic leukocytapheresis was applied to the treatment of inflammatory bowel disease (IBD) as early as the 1980s. Since then, the process has been further refined and 2 blood perfusion systems using membrane filtration are presently employed in Japan and Europe for the selective removal of leukocytes in patients with IBD: Cellsorba is a column of polyethylenephtarate fibers that captures lymphocytes and granulocytes, and Adacolumn is a column of cellulose acetate beads that selectively adsorb granulocytes and monocytes. These systems overcome the limitations of centrifugation. Leukocytapheresis has been shown to exert an overall anti-inflammatory effect, as peripheral leukocytes demonstrated a diminished capacity to produce inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, IL-8, and IL-1beta. In addition, down-regulation in the expression of adhesion molecule L-selectin and a shift toward a more immature granulocyte phenotype were observed in the peripheral blood. The safety and beneficial therapeutic effect of leukocytapheresis in IBD are being investigated further.

https://pubmed.ncbi.nlm.nih.gov/16378005/

Takuro Kanekura ¹, Katsuya Hiraishi, Koichi Kawahara, Ikuro Maruyama, Tamotsu Kanzaki

Ther Apher Dial 2006 Jun;10(3):247-56. doi: 10.1111/j.1744-9987.2006.00369.x.

In the present study, we have shown that granulocyte and monocyte adsorption apheresis (GCAP), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is useful for skin diseases attributable to activated granulocytes and psoriatic arthritis (PsA). We assessed the clinical effectiveness of GCAP and investigated the mechanisms underlying the adsorption of pathogenic granulocytes. The effect of GCAP was assessed in 14 patients with neutrophilic dermatoses and 16 with PsA. The mechanisms by which the instrument adsorbs activated granulocytes were investigated using an in vitro mini-column system that mimics the GCAP. Skin lesions and arthropathy improved in 22 of 29 patients (75.9%) and 14 of 18 (77.8%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, increased compared with normal subjects, was reduced by GCAP. In the mini-column system, CA beads adsorbed 50% neutrophils; and adsorption was inhibited significantly by treating plasma with EDTA and blood cells with antihuman CD11b monoclonal antibody. GCAP was useful for treating neutrophilic dermatoses and PsA. GCAP adsorbs Mac-1-expressing neutrophils to the CA beads by the binding of complement component (iC3b) on CA beads and CD11b expressed on activated neutrophils.

https://pubmed.ncbi.nlm.nih.gov/16817789/

Akira Andoh,Tomoyuki Tsujikawa,Osamu Inatomi,Yasuyuki Deguchi,Kazunori Hata,Katsuyuki Kitoh,Masaya Sasaki,Keiichi Mitsuyama,Yoshihide Fujiyama Therap Apher Dial(2005) 9, 2; 23-127, https://doi.org/10.1111/j.1774-9987.2005.00229.x

To elucidate the molecular mechanisms involved in the therapeutic effects of granulocyte/monocyte adsorption apheresis, changes were investigated in the cytokine responses of peripheral blood mononuclear cells (PBMC) before and after granulocyte/monocyte adsorptive apheresis in ulcerative colitis (UC) patients. Four patients with active UC were enrolled. All patients responded to granulocyte/monocyte adsorptive apheresis. A total of 20 sessions of four patients were analyzed. Peripheral blood mononuclear cells were isolated from peripheral venous blood within 5min before and after each session of granulocyte/monocyte adsorptive apheresis. The cells were stimulated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α for 24h, and the secreted IL-8 and IL-6 levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1β-induced IL-8 and IL-6 secretion was significantly decreased after granulocyte/monocyte adsorptive apheresis. TNF-α-induced IL-8 secretion was also significantly decreased after apheresis, but there was no significant difference in TNF-α-induced IL-6 secretion (P = 0.052). In conclusion, granulocyte/monocyte adsorptive apheresis down-regulates the IL-1β- and TNF-α-induced inflammatory responses in PBMC. The induction of hyporesponsiveness to pro-inflammatory cytokines may be an important factor mediating the clinical effects of granulocyte/macrophage adsorptive apheresis in UC patients.

https://pubmed.ncbi.nlm.nih.gov/15828923/

https://onlinelibrary.wiley.com/doi/10.1111/j.1774-9987.2005.00229.x

Russell D. Cohen

Gastroenterology2005 Vol. 128; Iss. 1 DOI:10.1053/j.gastro.2004.11.024

Clinical response rates in uncontrolled inflammatory bowel disease studies have commonly run in the 30%–50% range; as a result, early uncontrolled trials need validation from adequately blinded randomized trials before widespread application of such novel therapies. Although the long-term maintenance data from this study (60% at 8 months) is encouraging, further studies of the optimal interval for repeating apheresis for reinduction of remission or maintenance arealso in order. The potential for apheresis-based therapies as either a stand-alone strategy or in combination with other proven therapies in
the treatment of inflammatory bowel diseases also needs to be further elucidated. The promise of “no medications” for effective therapy in the treatment of ulcerative colitis is enticing, and perhaps a step closer, but clearly needs to be substantiated by larger controlled trials.

https://booksc.eu/book/20696837/914ad3

Tsukasa Nakamura ¹, Yasuhiko Kawagoe, Takaharu Matsuda, Akiko Ueda, Yoshihiko Ueda, Yutaka Takahashi, Araki Tanaka, Hikaru Koide Blood Purif  2004;22(6):499-504. doi: 10.1159/000081896. 

Background/aim: Increases in microalbuminuria and endothelin (ET-1) are involved in the development of ulcerative colitis (UC) and in its progress. Because granulocyte and monocyte adsorption apheresis has proven to be useful in the treatment of UC, we examined whether urinary albumin excretion and plasma ET-1 concentrations are altered and whether granulocyte and monocyte adsorption apheresis affects the concentrations of these two factors in patients with active UC. Methods: Twenty patients with active UC and 20 age-matched healthy volunteers (our hospital staffs) were included in this study. UC patients were randomly divided into two treatment groups: a granulocyte and monocyte adsorption treatment group (n = 10) and a conventional treatment group (n = 10). The urine albumin/creatinine ratio, plasma ET-1 concentration and tumor necrosis factor (TNF)-alpha were determined before and after treatment and compared between 2 treatment groups. The 10 adsorption treatment patients underwent 5 consecutive weekly apheresis sessions, each of 60 min duration at a flow rate of 30 ml/min. Results: The urine albumin/creatinine ratio in UC patients (6.4 +/- 2.2 mg/mmol) were higher than that in healthy subjects (1.0 +/- 0.7 mg/mmol, p < 0.01). In addition, the plasma ET-1 level in UC patients (3.5 +/-1.5 pg/ml) was higher than that in healthy subjects (0.8 +/- 0.4 pg/ml, p < 0.01). Plasma TNF-alpha was detected in UC patients (18.8 +/- 8.4 pg/ml), but not in healthy subjects. The urine albumin/creatinine ratio was highly correlated with the plasma ET-1 level (r = 0.62; p < 0.01) and plasma TNF-a level (r = 0.66, p < 0.01). Granulocyte and monocyte adsorption apheresis reduced the urine albumin/ creatinine ratio from 6.6 +/- 2.4 to 1.8 +/- 0.6 mg/mmol (p < 0.01), reduced the plasma ET-1 level from 3.7 +/- 1.6 to 1.4 +/- 0.6 pg/ml (p < 0.05) and reduced the plasma TNF-alpha from 19.2 +/- 8.6 to 3.8 +/- 1.2 pg/ml (p < 0.01). Conventional treatment did not affect these factors. Conclusion: Our data suggest that increases in the urine albumin/creatinine ratio, ET-1 and TNF-alpha play an important role in active UC and that granulocyte and monocyte adsorption apheresis is effective in ameliorating such increases.

https://pubmed.ncbi.nlm.nih.gov/15528877/

https://www.karger.com/Article/Abstract/81896