Tomoyuki Nakamura, Kazuhiro Moriyama, Toshikazu Sakai, Yu Kato & Osamu Nishida 

Ren Replace Ther 10, 51 (2024). https://doi.org/10.1186/s41100-024-00565-9

Background

Sepsis 3 definitions have shifted the focus from nonspecific inflammation to sepsis as an organ dysfunction caused by a dysregulated host response to infection. Neutrophils have become therapeutic targets because of their intimate but complex involvement in sepsis. We conducted ex vivo and animal experiments to apply a granulocyte and monocyte adsorption column, which is clinically used for inflammatory bowel disease, in sepsis. In this study, the biocompatibility was evaluated in sepsis-like hypercytokinemia.

Methods

Six female outbred pigs were anesthetized. Extracorporeal direct hemoperfusion (DHP) with an Adacolumn or a sham column was initiated after lipopolysaccharide (LPS) administration. The DHP was performed for 2 h at a blood flow rate (QB) of 30 or 60 mL/min. Blood samples were collected before and during the DHP (30, 60, 90, and 120 min). The percentage change in white blood cell count, platelet count, and cytokine concentration was compared between the Adacolumn and sham columns.

Results

The percentage change in white blood cells were 96 (95–98)% and 106 (101–108)% in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (p < 0.01). The percentage change in platelets were 95 (90–96)% and 97 (93–99)% in the in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (not significant; n.s.). At QB = 60 mL/min, the percentage change in tumor necrosis factor-α, interleukin (IL)-6, and IL-10 were 92 (81–106)%, 95 (93–102)%, and 98 (95–100)%, respectively, for the Adacolumn and 100 (95–102)%, 98 (87–104)%, and 97 (93–99)%, respectively, for the sham column. The percentage change in white blood cell counts, platelet counts, and all cytokines at QB = 30 and 60 mL/min showed similar trends.

Conclusion

The biocompatibility of the Adacolumn was evaluated using a porcine LPS-induced inflammation model. No decrease in platelet counts or significant cytokine production was observed, suggesting that the Adacolumn could be safely used in patients with sepsis with QB = 30–60 mL/min for 2 h. However, production of mediators other than cytokines remains unknown and requires further investigation.

Ang Cui ^1 2 3, Teddy Huang ⁴, Shuqiang Li ^5 4, Aileen Ma ^5 6, Jorge L Pérez ^5 6, Chris Sander ^5 7 8, Derin B Keskin ^5 4 9, Catherine J Wu ^5 9 10, Ernest Fraenkel ^5 11, Nir Hacohen ^12 13 14

Nature 2024 Jan;625(7994):377-384. doi: 10.1038/s41586-023-06816-9. Epub 2023 Dec 6.

Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets^1-3. A myriad of studies have highlighted their central role in immune function^4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1β induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.

Farah Yasmin ¹, Hala Najeeb ¹, Unaiza Naeem ¹, Abdul Moeed ¹, Thoyaja Koritala ², Salim Surani ^3 4

World J Clin Cases  2022 Jul 26;10(21):7195-7208. doi: 10.12998/wjcc.v10.i21.7195.

Inflammatory Bowel Disease (IBD) is a hallmark of leukocyte infiltration, followed by the release of cytokines and interleukins. Disease progression to Ulcerative Colitis (UC) or Crohn’s Disease (CD) remained largely incurable. The genetic and environmental factors disrupt enteral bacteria in the gut, which hampers the intestinal repairing capability of damaged mucosa. Commonly practiced pharmacological therapies include 5-aminosalicylic acid with corticosteroids and tumor necrosis factor (TNF)-α. New interventions such as CDP571 and TNF-blocking RDP58 report the loss of patient response. This review discusses the non-pharmacologic selective granulocyte-monocyte-apheresis (GMA) and leukocytapheresis (LCAP) that have been proposed as treatment modalities that reduce mortality. GMA, an extracorporeal vein-to-vein technique, presents a strong safety profile case for its use as a viable therapeutic option compared to GMA’s conventional medication safety profile. GMA reported minimal to no side effects in the pediatric population and pregnant women. Numerous studies report the efficacious nature of GMA in UC patients, whereas data on CD patients is insufficient. Its benefits outweigh the risks and are emerging as a favored non-pharmacological treatment option. On the contrary, LCAP uses a general extracorporeal treatment that entraps leukocytes and suppresses cytokine release. It has been deemed more efficacious than conventional drug treatments, the former causing better disease remission, and maintenance. Patients with UC/CD secondary to complications have responded well to the treatment. Side effects of the procedure have remained mild to moderate, and there is little evidence of any severe adverse event occurring in most age groups. LCAP decreases the dependence on steroids and immunosuppressive therapies for IBD. The review will discuss the role of GMA and LCAP.

https://pubmed.ncbi.nlm.nih.gov/36158031/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353887/

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.

https://www.gastrojournal.org/article/S0016-5085(20)33300-X/pdf

Elizabeth Staley, Joseph Schwartz, Huy P. Pham

https://www.researchgate.net/publication/330046385_Therapeutic_Leukocytapheresis_and_Adsorptive_Cytapheresis

Takuro Kanekura ¹, J Dermatol 2018 Aug;45(8):943-950

These actions render GMA a unique non-pharmacological treatment option for patients with chronic dermatoid conditions, which are difficult to treat with pharmacological preparations.

https://pubmed.ncbi.nlm.nih.gov/29782055/

Helena Rolandsdotter ^1 2, Kerstin Jönsson-Videsäter ^3 4, Ulrika L Fagerberg ^5 6, Michael Eberhardson ^1 7, Yigael Finkel ^1 2 , J Pediatr Gastroenterol Nutr. 2018 Apr;66(4):e103-e107.

We speculate that the decreases in colonic mucosal cytokine profiles after treatment may explain the observed clinical efficacy in the GMA-treated children with IBD.

https://pubmed.ncbi.nlm.nih.gov/28891831/

Belén Beltrán ^1 2 3, Esteban Sáez-González ¹, Inés Moret ^1 2 3, Francia C Díaz-Jaime ¹, Diego Alvarez-Sotomayor ¹, Elena Cerrillo ^1 2, Marisa Iborra ^1 2 3, Guillermo Bastida ^1 2 3, Mariam Aguas ^1 2 3, Pilar Nos ^1 2 3 , J Clin Apher. 2018 Feb;33(1):99-103

We hypothesize that GMA can help to lower the inflammatory load, thereby enhancing the effect of biologic drugs. 

https://pubmed.ncbi.nlm.nih.gov/28485025/

Shingo Kato, Akira Ishibashi, Kaori Sugiura, Kazuhito Kani, Tomonari Ogawa, Hajime Hasegawa, Koji Yakabi, Contrib Nephrol 2018;196:200-208.

GMA decreases inflammatory cytokines and upregulates regulatory T cells. Intensive GMA is significantly more effective than weekly GMA in patients with IBD. The frequency of GMA sessions per week positively correlates with treatment effects. GMA can be safely used in pregnant women and children because of its low adverse event rates. Maintenance therapy and rescue therapy for loss of response of anti-tumor necrosis factor (TNF)-α antibodies are effective. Optimal patients who responded to combination therapy with infliximab and GMA showed aggravation characteristics against infliximab treatment at week 4. Key Message: Prospective randomized blinded studies using a sham column should be performed for the loss of response against anti-TNF-α antibodies.

https://pubmed.ncbi.nlm.nih.gov/30041228/

Koji Sawada ¹ , Transfus Apher Sci. 2017 Oct;56(5):689-697.

Clinical studies with these two new models have shown good effects for active IBD. Clinical data suggest that leukocytapheresis might be an effective adjunct to therapy of IBD, to promote remission, taper conventional drug dosage and potentially should reduce the number of patients who require colectomy. The results may further understandings of the pathophysiology of IBD and this in turn should contribute to a more effective treatment of this disorder.

https://pubmed.ncbi.nlm.nih.gov/28986009/