Esteban Sáez-González ¹, Inés Moret ^2 3 4, Diego Alvarez-Sotomayor ², Francia Carolina Díaz-Jaime ², Elena Cerrillo ^2 3, Marisa Iborra ^2 3 4, Pilar Nos ^2 3 4, Belén Beltrán ^2 3 4 , Dig Dis Sci. 2017 Jun;62(6):1417-1425.

The benefit of cytapheresis appears to rest upon its ability to reduce levels of certain immune cell populations; however, whether this depletion results in further changes in lymphocyte populations and cytokine production needs further clarification. In this review, we aim to summarize existing evidence on the role of cytapheresis in patients with IBD, its effect on cytokine levels and cellular populations, and to discuss its potential impact on disease activity.

https://pubmed.ncbi.nlm.nih.gov/28432476/

Chiharu Tominaga ¹, Masaaki Yamamoto ¹, Yasutomo Imai ¹, Kiyofumi Yamanishi ¹ , Case Rep Dermatol. 2015 Feb 21;7(1):29-35.

 She is the oldest reported case of GPP with a deficiency of interleukin-36 receptor antagonist (DITRA), although GPP in DITRA has been suggested to usually occur in younger cases with no pre-existing psoriasis vulgaris.

https://pubmed.ncbi.nlm.nih.gov/25848350/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357681/pdf/cde-0007-0029.pdf

Koji Kamiya ¹, Yumi Aoyama ², Mariko Kawata ², Tetsuya Takiguchi ³, Seiko Mitsui ², Yoshiki Tokura ⁴, Keiji Iwatsuki ² , Eur J Dermatol. 2015 Apr;25(2):189-90.

https://pubmed.ncbi.nlm.nih.gov/26075324/

Takuya Bamba ¹, Takayuki Yamamoto, Satoru Umegae, Koichi Matsumoto, J Clin Apher. 2014 Apr;29(2):107-12.

Targeted extracorporeal granulocyte and monocyte apheresis (GMA) has produced clinical efficacy together with down modulation of specific inflammatory cytokines in patients with ulcerative colitis (UC). This study was to investigate if preoperative GMA produces immunological effect on dysregulated immune activity after restorative proctocolectomy (RPC) in patients with UC. Forty patients requiring RPC were included. Twenty randomly selected patients received five GMA sessions with the Adacolumn over two consecutive weeks before RPC (GMA group). RPC was performed within 2 weeks following the last GMA session. The other 20 patients did not receive GMA before RPC (non-GMA group). Blood samples were obtained immediately before surgery, at 1 h after surgery, and on postoperative Days 1, 3, and 7 from all patients. Abdominal exudate was obtained from the drainage tube at 1 h after surgery, and on postoperative Days 1, 3, and 7. Concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in plasma and peritoneal fluid from a drainage tube were measured by enzyme linked immunosorbent assay. Between the two groups, patients were matched with respect to age, sex, UC duration, severity, extent and the dose of prednisolone at surgery. IL-1β, IL-6, and TNF-α levels in plasma and peritoneal fluid were not significantly different between the two groups during the entire study period. Based on the assays of IL-1β, IL-6, and TNF-α levels in the plasma and the peritoneal fluid, this study did not find any effect on these inflammatory cytokines by preoperative GMA in patients with UC who underwent RPC.

https://pubmed.ncbi.nlm.nih.gov/24000140/

Yoko Yokoyama ¹, Ken Fukunaga ², Koji Kamikozuru ², Toshiyuki Sato ², Mikio Kawai ², Koji Nogami ², Kazuko Nagase ², Misaki Nakamura ², Masaki Immured ², Nobuyuki Hida ², Shiro Nakamura ² , Cytotherapy. 2014 Jun;16(6):821-5.

Immunosuppressive therapy required to treat an active CD potentially can promote HBV reactivation and worsen liver function. In this study involving a CD case complicated by chronic HBV infection, intensive GMA as a non-pharmacologic treatment intervention was associated with clinical remission and endoscopic improvement without HBV reactivation. Furthermore, GMA was well-tolerated and was without any safety concern. However, suppression of tumor necrosis and interleukin-6by GMA in this clinical setting is potentially very interesting.

https://pubmed.ncbi.nlm.nih.gov/24713332/

Shoichi Nishise ¹, Yasuhiko Abe, Eiki Nomura, Takeshi Sato, Yu Sasaki, Daisuke Iwano, Kazuya Yoshizawa, Makoto Yagi, Yuko Nishise, Yoshiyuki Ueno, Ther Apher Dial. 2014 Jun;18(3):252-7.

umor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

https://pubmed.ncbi.nlm.nih.gov/24965291/

Shoichi Nishise ¹, Takeshi Sato, Yu Sasaki, Ko Nagino, Daisuke Iwano, Takao Yaoita, Kazuya Yoshizawa, Yuko Nishise, Hiroaki Takeda, Ther Apher Dial. 2012 Oct;16(5):449-55.

Interleukin (IL)-10 is an anti-inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti-inflammatory intestinal macrophages with macrophage colony-stimulating factor (M-CSF). Thus, IL-10- and M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M-CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL-10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL-10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL-10 in the plasma was measured. Compared with the level in the Control group, plasma IL-10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL-10 production with monocyte adsorption stimuli. By increasing not only M-CSF but also IL-10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti-inflammatory intestinal macrophages.

https://pubmed.ncbi.nlm.nih.gov/23046370/

Tomomi Fujisawa ¹, Kana Murase, Hiroyuki Kanoh, Masao Takemura, Hidenori Ohnishi, Mariko Seishima, Ther Apher Dial. 2012 Oct;16(5):436-44.

Generalized pustular psoriasis (GPP) is a subtype of psoriasis with strong association with activated neutrophils. Adsorptive granulocyte and monocyte apheresis (GMA) is an extracorporeal intervention for selective depletion of activated granulocytes and monocytes. However, the immunological mechanism(s) for the effect of GMA on patients is not fully defined yet. We investigated the effects of GMA on the ratio of CD14(+) CD16(+) proinflammatory monocytes/CD14(+) monocytes and cytokine/chemokine production by these leukocytes including CXCL8, CCL2, CCL3, CCL4, CCL5 and tumor necrosis factor (TNF)-α in five patients with active GPP. CD14(+) CD16(+) monocytes were significantly elevated in patients with active GPP, and GMA markedly reduced the CD14(+) CD16(+) /CD14(+) ratio together with improvement of patients’ clinical symptoms. The serum levels of CXCL8, CCL3 and CCL4 were increased in active GPP patients. Likewise, CCL2 production from monocytes was increased in active GPP patients. Further, CCL3 and CCL4 production from monocytes in active GPP patients were reduced after a course of GMA. Serum CCL5 level and the release of CCL5 from monocytes in active GPP were significantly reduced, but TNF-α level in active GPP was similar to controls. Based on these results, we believe that in addition to neutrophils, elevated CD14(+) CD16(+) proinflammatory monocytes are part of the immune pathology in GPP. Accordingly, selective depletion of CD14(+) CD16(+) monocytes by GMA should be therapeutic in this condition.

https://pubmed.ncbi.nlm.nih.gov/23046368/

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/