Giorgos Bamias 1, Evanthia Zampeli 2, Eugeni Domènech 3 Expert Rev Gastroenterol Hepatol 2022 Jul 19;1-15. doi: 10.1080/17474124.2022.2100759.
Targeting neutrophils in inflammatory bowel disease: revisiting the role of adsorptive granulocyte and monocyte apheresis
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.
Cellular immune response triggered by granulocytoapheresis in ulcerative colitis patients under biological treatment
UEG WEEK VIRTUAL 2021
GMA induces specific immunoregulatory changes in leukocyte’s subpopulations. We confirm the depletion of the
monocytes with proinflammatory phenotype after GMA. Treg and B effector cells shift to a more immunotolerant phenotype. The emergence of subpopulations with the atypical immunofluorescence staining (CXCR3+CRTH2+) related to immature T cells support the immunomodulatory effects of GMA. These findings could help to understand the pathology of UC and to identify targeted immune subpopulations for treatment
Fecal Calprotectin is a Useful Biomarker for Predicting the Clinical Outcome of Granulocyte and Monocyte Adsorptive Apheresis in Ulcerative Colitis Patients: A Prospective Observation Study
Nobuhiro Ueno, Yuya Sugiyama, Yu Kobayashi, Yuki Murakami et al DOI: https://doi.org/10.21203/rs.3.rs-154609/v1
In summary, we demonstrated the utility of FC as a biomarker for assessing ER after GMA and predicting CR at the early phase during GMA in patients with active UC. Assessing the baseline characteristics alone before GMA was not sufficient to predict CR. Our findings will benefit patients with active UC by allowing them to avoid undergoing unnecessary invasive procedures and will help establish new GMA therapeutic strategies.
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.
Granulocyte and monocyte apheresis as an adjunctive therapy to induce and maintain clinical remission in ulcerative colitis: a systematic review and meta analysis
Szabolcs Kiss, Dávid Németh, Péter Hegyi , Mária Földi , Zsolt Szakács, Bálint Erőss , Benedek Tinusz , Péter Jenő Hegyi, Patrícia Sarlós , Hussain Alizadeh, BMJ Open 2021 May 19;11(5):e042374.
The results support the hypothesis that patients with active UC have a better chance of clinical remission if GMA is administered as an adjunctive therapy. As regards the frequency of AEs, we found no statistically significant difference between the two groups. With regard to remission maintenance, GMA was identified as an effective alternative therapeutic option
Physiological heating augments the anti-inflammatory reactions during granulocyte/monocyte apheresis: A in vitro study
Shoichi Nishise 1 2, Yuji Takeda 3, Yasuhiko Abe 1, Yu Sasaki 1, Shinichi Saitoh 3, Hidetoshi Nara 3, Hironobu Asao 3, Yoshiyuki Ueno, Ther Apher Dial 2020 Oct 17.
These results indicated that physiological heating of the apheresis carrier augmented the anti-inflammatory reaction in vitro. Thus, heating during GMA may be a new approach for augmenting clinical efficacy.
Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases
Maria K. Skytthe,1 Jonas Heilskov Graversen,1,* and Søren K. Moestrup, Int J Mol Sci. 2020 Aug; 21(15): 5497.
In conclusion, the specific targeting of CD163+ macrophages has been demonstrated to be a promising drug delivery strategy for handling inflammatory and malignant disease, contributing to the current pharmaceutical therapies.
Tu1292 EFFICACY OF GRANULOCYTE AND MONOCYTE ADSORPTIVE APHERESIS TREATMENT IS CORRELATED WITH COLONIC MUCOSAL EXPRESSION OF TH17-ASOCIATED CYTOKINES IN ULCERATIVE COLITIS
Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Shunsuke Komoto, Kengo Tomita, Ryota Hokari Gastroenterology 2020 158 (6) Suppl.S-1046
Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood, and it is used as induction therapy for IBD. However, its therapeutic mechanism has not been well characterized. Recently, it has been reported that Th17 releases chemokines which attract neutrophils, and some neutrophils produce IL17. We investigated that changes in mRNA expression levels of inflammation associated molecules such as cytokines, chemokines in colonic mucosa of ulcerative colitis (UC) patients before and after GMA treatment in order to obtain further understanding of GMA therapeutic mechanisms. Methods: Thirty-two active UC patients (Mayo score ≥ 5 and Mayo endoscopic score ≥ 2) and 10 non-IBD control subjects were enrolled in this study. All UC patients received 10 times of GMA, and colonoscopies were applied before the first GMA and after the last GMA. Control subjects underwent colonoscopies for screening of colon cancer. Assessment of GMA therapeutic efficacy was determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. Results: GMA treatment efficacy is 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) were response and 4 patients (12.5%) were non-response. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In the remission group, mRNA levels in mucosal tissue of IL1β, IL6, IL17, IL23 and GM-CSF which are Th17-asociated cytokines significantly decreased after the last GMA compared to the baseline levels(P<0,05) in contrast, expression of these mRNA tended to increase following GMA treatment in the non-response group. On the other hand, IL12 and IFN- γ which are associated with Th1 did not significantly decrease in the remission group. mRNA levels of leukocyte trafficking associated molecules such as MAdCAM-1, ICAM-1, integrinβ7, IL8 and MIP-1β significantly decreased following GMA treatment in the remission group(P <0.05), whereas only IL8 mRNA expression in the non-response group tended to increase. IL1 β, IL6, GM-CSF which are Th17-asociated cytokines and IL8 mRNA expressions in post-GMA treatment were significantly higher in the non-response group compared to the remission group or control group(P <0.05). Conclusion: In UC patients who achieved clinical remission by GMA, Th17- associated cytokines and leukocyte trafficking associated molecules but not Th1-asociated cytokines decreased significantly. Furthermore, Th17-asociated cytokines increased in the non-responders. These results reaffirm the involvement of neutrophil in the pathophysiology of UC and could be helpful for characterizing of GMA therapeutic mechanism.
SA6-03 MicroRNA and granulocyte and monocyte adsorption apheresis on neutrophilic skin diseases
Yuko Higashi, Munekazu Yamakuchi, Takuro Kanekura
poster at ISFA 2019 pag 126
Neutrophilic skin diseases are a group of disorders characterized by intense dermal infiltration of neutrophils without infection. They include a variety of diseases, such as pyoderma gangrenosum, pustular psoriasis, and palmoplantar pustulosis. We demonstrated that granulocyte and monocyte adsorption apheresis (GMA) is a useful treatment modality for such refractory skin diseases. Microarray analysis of microRNAs (miRNAs) was performed using sera of patients with neutrophilic skin diseases before and after GMA. Several miRNAs significantly increased in patients compared to control subjects. The expression of three
miRNAs decreased after apheresis, suggesting that these miRNAs might be involved in the pathogenesis of neutrophilic skin decreases. To prove the function of these miRNAs, HL-60, a human acute promyelocytic leukemia cell line, was differentiated by the treatment of alltrans retinoic acid (ATRA). When HL-60 was differentiated to neutrophilic cells, the HEstaining shows an increased cytoplasm to nucleus ratio, condensated chromatin, and nuclear segmentation. The expression of three miRNAs increased during the neutrophilic differentiation. Stimulation of ATRA-treated HL-60 by some cytokines altered miRNA expressions. Moreover, manipulation of these miRNAs changed proliferation of cultured keratinocytes. These data
suggest that miRNAs play an important role in regulating neutrophilic differentiation and proliferation of keratinocytes in case of neutrophilic disorders such as psoriasis. These miRNAs could be markers of disease severity and response of GMA.
Tu1846 Higher TNFα and Mip-1β Expression in Pretreatment Colonic Mucosa Have Potential to Predict of Achieving Mucosal Healing by Granulocyte and Monocyte Adsorptive Apheresis Therapy in Ulcerative Colitis Patients
Chie Kurihara, Toshihide Ohmori, Hirotaka Furuhashi, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Gastroenterology 2019 156 (6) Suppl. S-1146
Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood. GMA is effective and safe as induction therapy in ulcerative colitis (UC) of moderate to severe patients, and commonly used in Asia and north Europe. However, therapeutic mechanism of GMA, especially its effect on mucosal healing, has not been well characterized. Since moderate to severe patients with UC sometimes become fulminant, it is important to select an appropriate induction therapy. GMA treatment efficacy is reported about 60% patients respond, whereas, there is not useful parameter that predicts GMA therapeutic efficacy before treatment. In this study, we attempted to identify predictive factors of clinical response to GMA treatment in UC patients. Methods: Thirty-two active UC patients (Mayo score ^ 5 and Mayo endoscopic score ^ 2) and 10 non-IBD control subjects were enrolled in this study. All UC patients received 10 or 11 times of GMA, and colonoscopies were applied before the first GMA and after the last GMA. Control subjects underwent colonoscopies for screening of colon cancer. Assessment of disease activity and colonic mucosal healing were determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. ROC curves analysis was used to assess sensitivity and specificity in prediction of GMA therapeutic efficacy. Results: GMA treatment efficacy is 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) were response and 4 patients (12.5%) were non-response. Mucosal healing was observed in 18 patients (56.3%) and it was not observed in 14 patients (43.7%). Baseline characteristics were not significantly different according to GMA efficacy. Before the first GMA session, the clinical remission group showed significantly higher expressions of TNFα, MAdCAM-1 and MIP-1β mRNA than those of the non-response group (P <0.05). Patients in the response group who highly expressed these mRNA achieved mucosal healing. In the mucosal healing group, the mRNA levels of TNFα, IL-1β, IL-8, MIP-1β, TGFβ and IL-10 were significantly higher than those in the non-mucosal healing group (P <0.05). TNFα and MIP-1β had 0.83 and 0.79 of area under the curve with 83.3% and 66.7% sensitivity, 71.4% and 100% specificity, 78.9% and 100%positive predictive value, and 76.9% and 70.0% negative predictive value, respectively, for prediction of mucosal healing. Conclusion: Mucosal expression of TNFα and MIP-1β mRNA before treatment in the remission group and the mucosal healing group was significantly higher than non-responder to GMA treatment. We propose that measuring of these molecules’ expression is useful to expect GMA therapeutic efficacy in patients with UC.
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