Therapeutic leukocytapheresis for inflammatory bowel disease

doi:10.1016/j.transci.2007.08.003

Transfusion and Apheresis Science

Volume 37, Issue 2, October 2007, Pages 191-200

https://doi.org/10.1016/j.transci.2007.08.003 Get rights and content

Abstract

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.

Section snippets

Inflammatory bowel disease

Inflammatory bowel disease (IBD) like ulcerative colitis (UC) and Crohn’s disease (CD) is a debilitating chronic relapsing-remitting disorder that afflicts millions of individuals throughout the world and produces symptoms which impair ability to function and quality of life. UC is confined primarily to the colon and the rectum, while CD can affect any part of the gut from the mouth to the perianal region; up to 65% of patients with CD have the disease affecting the small intestine [1], [2].

Peripheral blood leukocytes in IBD

Blood leukocytes are best known for their role in the defense of the body against pathogens as well as against certain diseases like cancer. However, leukocytes when activated show an amazing plasticity with respect to the diversity of their function and its magnitude. Further, as seen in Fig. 1, patients with active IBD may harbour elevated peripheral neutrophils [14] in the presence of compromised lymphocytes [15], [16], [17]. Additionally, in IBD, neutrophils show activation behaviour [18]

Effects of Adacolumn on peripheral blood leukocytes

The Adacolumn is filled with cellulose acetate beads of 2 mm in diameter as the column leukocytapheresis carriers; the beads are bathed in physiologic saline [14]. The carriers remove from blood in the column most of the granulocytes (neutrophils, eosinophils and basophils) and the monocytes/macrophages together with some platelets; lymphocytes are spared (Fig. 2). In fact lymphocytes increase (Fig. 1) [14], [16], [17]. The merits of sparing lymphocytes are discussed below. The Adacolumn is an

Clinical efficacy associated with Adacolumn in patients with UC

In Japan, the Adacolumn was approved by the Ministry of Health in April 2000 for the treatment of UC. Further, Adacolumn is CE marked [14] and therefore it is available in the EU countries for clinical application. In recent years, there has been an evolution of reports (reviewed in Ref. [31]) mainly from Japan and also from Europe on the clinical efficacy of Adacolumn in patients with IBD. The clinical data show that GMA in patients with steroid dependent or steroid refractory UC was

GMA in the treatment of patients with Crohn’s disease

Most of the published studies so far have reported on the efficacy of GMA in patients with UC [14], [16], [17], [30], [31], [32], [33], [34], [35], [36], [37], [38]. However, GMA seems to produce significant efficacy in patients with active CD as well [39], [40], [41], [42]. The first study in CD was reported by Matsui et al. [41] on seven patients who were refractory to standard medications, each received five GMA sessions. Five of seven patients achieved remission. Subsequently, Fukuda et al.

Searching for the most effective dosage of GMA

Needless to say that the evolution of modern medicine has relied on the outcomes of clinical trials to determine the dosage of drugs with maximum efficacy margin and minimum adverse effect. Fortunately for GMA, which is a non-drug treatment strategy, reliance on clinical trial outcomes has been less demanding or at least lack of it has not caused serious side effects. Nonetheless, it is natural that knowing the most effective frequency and the number of GMA sessions for patients with mild,

Knowing the best responders to GMA

Available data suggest that steroid naive patients respond particularly well to GMA [16], [32], [44]. Characteristically they respond faster with fewer GMA sessions and have a higher cumulative rate of remission [16], [31], [44]. Thus, the remission rate in a cohort of 20 steroid naïve patients reported by Suzuki et al. [16] was an 85%. Similarly, Tanaka et al. [44] treated a cohort of 45 patients, 26 steroid naive and 19 steroid dependent. Each patient could receive up to a maximum of 11 GMA

GMA for suppressing clinical relapse

To prevent a disease episode from flaring up has obvious advantages. Firstly, morbidity is intercepted and secondly, medical care during early stages of the flare up is spared. Based on this thinking, Bjarnason el al. [45] at GKT in London identified patients at a high risk of clinical relapse on the basis of a very high faecal calprotectin level, a neutrophil selective protein that provides quantitative measure of intestinal neutrophil level and inflammation [22]. This study, randomly assigned

Immunomodulation associated with Adacolumn GMA

The Adacolumn depletes excess peripheral granulocytes and monocytes/macrophages. However, the clinical efficacy associated with a course of GMA is unlikely to reflect its effects on peripheral leukocytes per se. Accordingly, it is inferred that additional mechanisms of actions might follow a course of GMA. As reviewed above, leukocytes that bear the FcγR and complement receptors adhere to the GMA carriers [29], [30]. The adsorbed leukocytes release an array of substances both toxic and

The merits of sparing lymphocytes in IBD

To say that currently, the circulating level and functions of a subpopulation of T lymphocytes, CD4⁺CD25⁺ expressing Foxp3 (CD4⁺CD25⁺Foxp3⁺) define IBD better than any other immunologic marker is not an over statement. The CD4⁺CD25⁺ phenotype is known as naturally arising regulatory T cell (Treg) and any pharmacologic preparation that can increase the frequency of the CD4⁺CD25⁺ phenotype is believed to have an unparallel impact on the treatment of IBD [56], [57], [58], [59]. Functional CD4⁺CD25⁺

Concluding remarks

Patients with IBD have activated granulocytes and monocytes/macrophages, which are thought to be major factors in the exacerbation and perpetuation of the disease and warrant to be targets of therapy. In line with this understanding, GMA in patients with IBD has been associated with significant clinical efficacy together with a sustained suppression of specific inflammatory profiles including TNF-α and the proinflammatory CD14⁺CD16⁺ phenotype. Further, GMA has been followed by an increase in

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Cited by (72)

An in vitro analysis of the interaction between infliximab and granulocyte–monocyte apheresis
2024, Gastroenterologia y Hepatologia
Primary non-response and secondary loss of response to anti-TNF agents are common in inflammatory bowel disease. Increasing drug concentrations are correlated to better clinical response and remission rates. Combination of granulocyte–monocyte apheresis (GMA) with anti-tumor necrosis factor (TNF) agents could be an option in these patients. The objective of our study was to perform an in vitro assay to determine if the GMA device can lead to infliximab (IFX) adsorption.
A blood sample was obtained from a healthy control. It was incubated with three concentrations of IFX (3, 6, and 9 μg/ml) at room temperature for 10 min. At that time, 1 ml was collected to determine the IFX concentration. Then, 10 ml of each drug concentration was incubated with 5 ml of cellulose acetate (CA) beads from the GMA device at 200 rpm for 1 h at 37 °C to simulate physiological human conditions. A second sample of each concentration was collected and IFX levels were determined.
No statistically significant differences were observed in the IFX levels in the blood samples before and after incubation with the CA beads (p = 0.41) and after repeated measurements (p = 0.31). Mean change was 3.8 μg/ml.
The in vitro combination of GMA and IFX did not change the circulating levels of IFX at the three concentrations tested, suggesting that there is no interaction between the drug and the apheresis device in vitro and that they might be safely combined with each other.
La falta de respuesta primaria y la pérdida de respuesta secundaria a los agentes antifactor de necrosis tumoral (TNF) son comunes en la enfermedad inflamatoria intestinal. El aumento de los niveles de fármaco se correlaciona con una mejor respuesta clínica y de las tasas de remisión. La combinación de la aféresis selectiva de granulocitos y monocitos (GMA) con agentes anti-TNF podría ser una opción en estos pacientes. El objetivo de nuestro estudio fue realizar un ensayo in vitro para determinar si el dispositivo de GMA puede interaccionar con infliximab (IFX).
Se obtuvo una muestra de sangre de un control sano. Se incubó con 3 concentraciones de IFX (3, 6 y 9 μg/ml) a temperatura ambiente durante 10 minutos. En ese momento, se recogió 1 ml para determinar la concentración de IFX. Luego, se incubaron 10 ml de cada concentración de fármaco con 5 ml de cuentas de acetato de celulosa del dispositivo GMA a 200 rpm durante una hora a 37 °C para simular las condiciones fisiológicas humanas. Se recogió una segunda muestra de cada concentración y se determinaron los niveles de IFX.
No se observaron diferencias estadísticamente significativas en los niveles de IFX en las muestras de sangre antes y después de la incubación con las cuentas de acetato de celulosa (p = 0,41) ni tras mediciones repetidas (p = 0,31). La media de cambio fue de 3,8 μg/ml.
La combinación in vitro de IFX y GMA no modificó los niveles circulantes del fármaco en las 3 concentraciones probadas, lo que indica que no existe interacción entre el fármaco y el dispositivo de aféresis in vitro y que podrían combinarse de forma segura.
Combination of granulocyte–monocyte apheresis and tofacitinib: Multicentre and retrospective study
2024, Gastroenterologia y Hepatologia
Granulocyte–monocyte apheresis (GMA) has shown to be safe and effective in treating ulcerative colitis (UC), also in combination with biologics. The objective of this study is to evaluate the efficacy and safety of combining GMA after primary non-response (PNR) or loss of response (LOR) to tofacitinib (TOFA) in patients with UC.
Retrospective study including all patients with refractory UC who received GMA plus TOFA. Efficacy was assessed 1 and 6 months after finishing GMA by partial Mayo score, C-reactive protein (CRP) and fecal calprotectin (FC). Descriptive statistics and non-parametric tests were used in the statistical analysis.
Twelve patients were included (median 46 years [IQR, 37–58]; 67% female; 67% E3). Patients were mostly receiving TOFA 10 mg bid (75%), and 33% also concomitant steroids at baseline. Median partial Mayo score at baseline was 7 (IQR, 5–7), and it decreased to a median of 2 (IQR, 0–3) and 0 (IQR, 0–3) after 1 and 6 months (p = 0.027 and 0.020, respectively), while no differences were found in CRP and FC. Clinical remission was achieved by 6 patients both at 1 (50%) and 6 months (67%). CF values < 250 mg/kg were achieved by 2 and 4 patients at 1 and 6 months (data available in 5 and 7 patients, respectively). No patient required dose-escalation of TOFA, and one patient was able to de-escalate the drug. No patient required colectomy and all patients under steroids were able to stop them.
The combination of GMA and TOFA can be effective in selected cases of UC after PNR or LOR to this drug.
La aféresis de granulocitos-monocitos (GMA) ha demostrado ser segura y eficaz en el tratamiento de la colitis ulcerosa (CU), incluso en combinación con fármacos biológicos. El objetivo de este estudio es evaluar la eficacia y la seguridad de combinar GMA con tofacitinib (TOFA) tras falta de respuesta primaria o pérdida de respuesta a este fármaco en pacientes con CU.
Estudio retrospectivo que incluyó a todos los pacientes con CU refractaria que recibieron GMA más TOFA. La eficacia se evaluó 1 y 6 meses después de finalizar la GMA mediante la puntuación de Mayo parcial, la proteína C reactiva (PCR) y la calprotectina fecal (CF). El análisis estadístico se realizó mediante parámetros descriptivos y pruebas no paramétricas.
Se incluyeron doce pacientes (mediana 46 años [RIQ, 37-58]; 67% mujeres; 67% E3). En el momento basal, la mayoría de los pacientes estaban recibiendo TOFA 10 mg dos veces al día (75%), y el 33% también recibían esteroides concomitantes. La mediana de la puntuación de Mayo parcial basal fue de 7 (RIC, 5-7), y disminuyó a una mediana de 2 (RIC, 0-3) y 0 (RIC, 0-3) tras 1 y 6 meses (p = 0,027 y 0,020, respectivamente), mientras que no se encontraron diferencias en la PCR y la CF. Se logró remisión clínica en 6 pacientes tanto al mes (50%) como a los 6 meses (67%). Dos y 4 pacientes alcanzaron valores de CF < 250 mg/kg el mes 1 y el 6 (datos disponibles en 5 y 7 pacientes, respectivamente). Ningún paciente requirió aumentar la dosis de TOFA y un paciente pudo reducirla. Ningún paciente necesitó colectomía y todos los pacientes tratados con esteroides pudieron suspenderlos.
La combinación de GMA y TOFA puede ser eficaz en casos seleccionados de CU tras la falta de respuesta primaria o pérdida de respuesta a este fármaco.
Isochlorogenic acid A alleviates dextran sulfate sodium-induced ulcerative colitis in mice through STAT3/NF-кB pathway
2023, International Immunopharmacology
Isochlorogenic acid A (ICGA-A) is a dicaffeoylquinic acid widely found in various medicinal plants or vegetables, such as Lonicerae japonicae Flos and chicory, and multiple properties of ICGA-A have been reported. However, the therapeutic effect of ICGA-A on colitis is not clear, and thus were investigated in our present study, as well as the underlying mechanisms. Here we found that ICGA-A alleviated clinical symptoms of dextran sodium sulfate (DSS) induced colitis model mice, including disease activity index (DAI) and histological damage. In addition, DSS-induced inflammation was significantly attenuated in mice given ICGA-A supplementation. ICGA-A reduced the fraction of neutrophils in peripheral blood and the infiltration of neutrophils and macrophages in colon tissue, and reduced pro-inflammatory cytokine production and tight junctions in mouse models. Furthermore, ICGA-A down-regulated expression of STAT3 and up-regulated the protein level of IκBα. Our in vitro studies confirmed that ICGA-A inhibited the mRNA expression of pro-inflammatory cytokines. ICGA-A blocked the phosphorylation of STAT3, p65, and IκBα, suppressed the expression STAT3 and p65. In addition, the present study also demonstrated that ICGA-A had no obvious toxicity on normal cells and organs. Taken together, we conclude that ICGA-A mitigates experimental ulcerative colitis (UC) at least in part by inhibiting the STAT3/NF-кB signaling pathways. Hence, ICGA-A may be a promising and effective drug for treating UC.
Factors associated with treatment outcome, and long-term prognosis ofpatients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: A prospective multicenter study
2015, Cytotherapy
Citation Excerpt :
Accordingly, a new concept has emerged pointing to inflammatory cytokines as a major therapeutic target for treating IBD. However, given that inflammatory cytokines are generated by activated cellular elements including monocytes and granulocytes within the patients' own circulation or resident within the inflamed mucosa [9,19,31], depletion of activated granulocytes and monocytes by GMA should be an ideal non–drug-based therapeutic strategy for IBD patients. It should be logical to assume that depletion of TNF-producing activated leucocytes should at least normalize patients' immune profile and enhance drug efficacy.
Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined.
In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) ≤3 meant remission, and response meant CAI decreased by ≥3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ).
After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse.
Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well.
Crohn's disease complicated by hepatitis B virus successfully treated with the use of adsorptive depletion of myeloid lineage leucocytes to suppress inflammatory cytokine profile
2014, Cytotherapy
In patients with inflammatory bowel disease infected with hepatitis B virus (HBV), immunosuppressive therapy required to suppress active inflammatory bowel disease may promote HBV reactivation.
A 27-year-old corticosteroid-naive woman with Crohn's disease (CD) activity index of 249.8 complicated by HBV infection was offered Entecavir to control HBV reactivation during immunosuppressive therapy for CD. The patient refused Entecavir, fearing that it might adversely affect her pregnancy outcome. Instead, we applied intensive granulocyte/monocyte adsorptive apheresis (GMA) at two sessions per week to deplete inflammatory cytokine-producing leucocytes as an immunosuppressive therapy in this case.
GMA induced stable remission (CD activity index, I 105) and endoscopic improvement without HBV reactivation or safety concern. Furthermore, CD remission was paralleled by suppression of tumor necrosis factor and interleukin as measured in serum samples.
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.
Adsorptive cytapheresis in ulcerative colitis: A non-pharmacological therapeutic approach revisited
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^☆: Presented at the XXXIII Congress of the European Society for Artificial Organs (ESAO) and the European Society for Haemapheresis (ESFH) held in Umea, Sweden, 21–24 June 2006.

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Therapeutic leukocytapheresis for inflammatory bowel disease☆

Abstract

Section snippets

Inflammatory bowel disease

Peripheral blood leukocytes in IBD

Effects of Adacolumn on peripheral blood leukocytes

Clinical efficacy associated with Adacolumn in patients with UC

GMA in the treatment of patients with Crohn’s disease

Searching for the most effective dosage of GMA

Knowing the best responders to GMA

GMA for suppressing clinical relapse

Immunomodulation associated with Adacolumn GMA

The merits of sparing lymphocytes in IBD

Concluding remarks

Lancet

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

Immunol Today

Gastroenterology

Clin Gastroenterol Hepatol

Am J Gastroenterol

Immunol Today

Gastroenterology

Gastroenterology

Dietary antigens as aggravating factors in Crohn’s disease

Dig Dis Sci

How effective is current medical therapy for severe ulcerative colitis?

J Clin Gastroenterol

Sulphasalazine-adverse effects and desensitization

Dig Dis Sci

How to do without steroids in inflammatory bowel disease

Inflamm Bowel Dis

Nutrition and gastrointestinal disease

Scand J Gastroenterol (Suppl)

Can Cyclosporine go it alone in severe ulcerative colitis

Curr Gastroenterol Rep

Review article: a critical approach to new forms of treatment of Crohn’s disease and ulcerative colitis

Aliment Pharmacol Ther

Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration

Arthritis Rheum

Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes

Ther Apher Dial

The role of peripheral lymphocytes in the prediction of recurrence in Crohn’s disease

Surg Gynecol Obstet.

Selective neutrophil and monocyte adsorptive apheresis as a first line treatment for steroid naïve patients with active ulcerative colitis: a prospective uncontrolled study

Dig Dis Sci

Adacolumn selective leukocyte adsorption apheresis in patients with active ulcerative colitis: clinical efficacy, effects on plasma IL-8 and the expression of toll like receptor 2 on granulocytes

Dig Dis Sci

Peripheral blood neutrophils in inflammatory bowel disease: morphological evidence of in vivo activation in active disease

Clin Exp Immunol

Neutrophil apoptosis is delayed in patients with inflammatory bowel disease

Shock

Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators

J Leukoc Biol

Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes

J Immunol

Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease

Lancet

Role of cytokines in the pathogenesis of inflammatory bowel disease

Annu Rev Med

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin-10 during intestinal inflammation

Gut

IL-23: a master regulator in Crohn’s disease

Nat Med