Toshimi Chibaa, Mikiya Endob, Shoko Matsushitab, Mika Sasakib, Shoichi Chidab, Yosuke Toyaa, Satoshi Kasugaia, Nozomi atsudaa, Shunsuke Orikasaa, Yukito Abikoa, Norihiko Kudaraa, Shuhei Oanaa, Masaki Endoa, Kazuyuki Suzukia© 2011 S. Karger AG, BaselISSN 1662–0631

Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn’s disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250654/pdf/crg0005-0667.pdf

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/

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/

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

Takayuki Yamamoto ¹, Abbi R Saniabadi, Satoru Umegae, Koichi Matsumoto, Inflamm Bowel Dis. 2006 Aug;12(8):719-26.

Depleting granulocytes and monocytes/macrophages by SLA should mitigate cytokine profiles in the intestinal mucosa and correct an imbalance between pro- and anti-inflammatory cytokines in active UC.

https://pubmed.ncbi.nlm.nih.gov/16917227/

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

Hiroyuki Hanai ¹, Fumitoshi Watanabe, Masami Yamada, Yoshihiko Sato, Ken Takeuchi, Takayuki Iida, Kotaro Tozawa, Tatsuo Tanaka, Yasuhiko Maruyama, Isao Matsushita, Yasushi Iwaoka, Abby Saniabadi, Am J Gastroenterol. 2004 Aug;99(8):1532-8.

The sources of s-RI/RII are believed to be activated monocytes and neutrophils with further release when these leukocytes adhere to the column carriers. s-RI/RII released during GMA should contribute to the clinical efficacy of this procedure.

https://pubmed.ncbi.nlm.nih.gov/15307873/

Nobuhito Kashiwagi ¹, Minoru Nakano, Abby R Saniabadi, Masakazu Adachi, Toshikazu Yoshikawa

Inflammation 2002 Aug;26(4):199-205. doi: 10.1023/a:1016523914161.

In active rheumatoid arthritis, large numbers of granulocytes and macrophages are found in the inflamed joints. These leucocytes can promote inflammation and tissue injury by releasing inflammatory cytokines, proteinases and oxygen derivatives. To see if granulocyte and monocyte (GM) depletion produces anti-inflammatory effect, GM adsorption apheresis was performed in rabbits with immune arthritis by using a column (Adacolumn) filled with cellulose diacetate beads (G-1 beads) as adsorptive carriers which selectively adsorb CD11b positive GMs. Injection of ovalbumin into the knee joints of ovalbumin-sensitized rabbits caused a marked increase in peripheral blood leucocytes, joint swelling, increased granulocyte adhesion to G-1 beads and elevated TNF-alpha production by peripheral blood mononuclear cells (PBMC). When rabbits received a 60 min adsorption apheresis, there was suppression of CD11b positive leucocyte infiltration into the joint and reduced joint swelling (P < 0.01) compared with controls. Additionally, there was a significant (p < 0.01) suppression of TNF-alpha production by PBMC in the post column blood. These results suggest that GM depletion may serve as a non-pharmacological strategy to modify inflammatory disorders.

https://pubmed.ncbi.nlm.nih.gov/12184634/

Nobuhito Kashiwagi ¹, Minoru Nakano, Abby R Saniabadi, Masakazu Adachi, Toshikazu Yoshikawa

Inflammation 2002 Aug;26(4):199-205. doi: 10.1023/a:1016523914161.

In active rheumatoid arthritis, large numbers of granulocytes and macrophages are found in the inflamed joints. These leucocytes can promote inflammation and tissue injury by releasing inflammatory cytokines, proteinases and oxygen derivatives. To see if granulocyte and monocyte (GM) depletion produces anti-inflammatory effect, GM adsorption apheresis was performed in rabbits with immune arthritis by using a column (Adacolumn) filled with cellulose diacetate beads (G-1 beads) as adsorptive carriers which selectively adsorb CD11b positive GMs. Injection of ovalbumin into the knee joints of ovalbumin-sensitized rabbits caused a marked increase in peripheral blood leucocytes, joint swelling, increased granulocyte adhesion to G-1 beads and elevated TNF-alpha production by peripheral blood mononuclear cells (PBMC). When rabbits received a 60 min adsorption apheresis, there was suppression of CD11b positive leucocyte infiltration into the joint and reduced joint swelling (P < 0.01) compared with controls. Additionally, there was a significant (p < 0.01) suppression of TNF-alpha production by PBMC in the post column blood. These results suggest that GM depletion may serve as a non-pharmacological strategy to modify inflammatory disorders.

https://pubmed.ncbi.nlm.nih.gov/12184634/

Yuriko Tsukada ¹, Tetsuo Nakamura, Mitsutoshi Iimura, Bun-ei Iizuka, Naoaki Hayashi, Am J Gastroenterol. 2002 Nov;97(11):2820-8.

IL-8 mRNA was significantly increased in inflamed mucosa of UC. Patients with high IL-8 mRNA expression in colonic mucosa despite PSL treatment were responsive to GCAP. Therefore, quantitative measurement of mucosal IL-8 mRNA may be useful in predicting the response to GCAP.

https://pubmed.ncbi.nlm.nih.gov/12425554/