An Open-Label Pilot Study of Granulocyte Colony-Stimulating Factor for the Treatment of Severe Endoscopic Postoperative Recurrence in Crohn’s Disease

Dejaco, Clemens; Lichtenberger, Conny; Miehsler, Wolfgang; Oberhuber, Georg; Herbst, F.; Vogelsang, Harald; Gangl, Alfred; Reinisch, Walter

doi:10.1159/000074517

Cited by 46 publications

(33 citation statements)

References 21 publications

(27 reference statements)

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“…The rationale for these latter agents includes reports describing beneficial effects from G-CSF or granulocyte-macrophage CSF for inflammatory bowel disease in the setting of chronic granulomatous disease, glycogen storage disease Ib, and Crohn disease, [29][30][31][32][33] and reports that G-CSF may be beneficial as adjunctive therapy for infections in nonneutropenic patients, including those with abnormal neutrophil function such as diabetics. 34 It should also be noted that short-term (1-7 days) G-CSF administration to healthy volunteers is reported to increase expression of phagocytic receptors, phagocytosis, oxidative activity, and microbial killing by neutrophils 34 ; however, little information is available as to its effects on neutrophil function when used on a chronic basis other than for patients with inherited neutropenia syndromes, 35,36 who are not a comparable group.…”

Section: Patient Historymentioning

confidence: 99%

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Matute

Arias

Wright

et al. 2009

Blood

363

268

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Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91 phox and p22 phox , which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47 phox and p67 phox . A fifth subunit, p40 phox , plays an important role in phagocytosisinduced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40 phox , in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40 phox R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40 phox -deficient granulocytes, with premature loss of p40 phox R105Q from phagosomes. Thus, p40 phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease. IntroductionSuperoxide production by the phagocyte NADPH oxidase during the respiratory burst is an essential component of the innate immune response. The active enzyme is assembled from a membrane-bound flavocytochrome b, a heterodimer composed of gp91 phox and p22 phox subunits, and cytosolic regulatory components p47 phox , p67 phox , p40 phox , and the Rac GTPase. 1,2 Genetic defects in the NADPH oxidase cause chronic granulomatous disease (CGD), characterized by absent or markedly reduced enzyme activity, recurrent bacterial and fungal infections, and granulomatous inflammation that can involve multiple organs, including the genitourinary and gastrointestinal tracts. 1,3 Recent retrospective studies report clinical and genetic findings on more than 900 patients. [4][5][6][7] Although there is some ethnic and regional variation, approximately two-thirds of CGD patients have recessive mutations in the X-linked CYBB gene encoding gp91 phox , and the remainder have autosomal recessive defects in CYBA, NCF1, or NCF2, encoding p22 phox , p47 phox , or p67 phox , respectively. Mutations involving p40 phox or Rac have not been reported as causes of CGD. An infant with a dominant-negative mutation in the hematopoietic-specific Rac2 GTPase was reported, with partial oxidase defects, markedly impaired leukocyte migration and adhesion, and a clinical picture that resembled leukocyte adhesion deficiency rather than CGD. 8,9 In the majority of CGD cases, the gen...

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Section: Patient Historymentioning

confidence: 99%

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Matute

Arias

Wright

et al. 2009

Blood

363

268

View full text Add to dashboard Cite

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“…The randomized trial of granulocyte macrophage colony-stimulating factor in active disease was affected by a high placebo response rate, but the treatment did appear efficacious [146]. If used in remission or in the post-operative setting to prevent lesions developing, these therapies may be more effective [147]. The identification of novel therapeutic targets may also improve results.…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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“…Promising preclinical data have been translated recently into the treatment of human inflammatory bowel disease. G-CSF proved to be efficacious in severe endoscopic postoperative recurrence of Crohn's disease (67). Five patients were treated with 300 g of recombinant human G-CSF three times per week for 12 wk.…”

Section: G-csf In Inflammatory Bowel Diseasementioning

confidence: 99%

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

Rutella

Zavala

Danese

et al. 2005

The Journal of Immunology

201

154

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In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.

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An Open-Label Pilot Study of Granulocyte Colony-Stimulating Factor for the Treatment of Severe Endoscopic Postoperative Recurrence in Crohn’s Disease

Cited by 46 publications

References 21 publications

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Crohn’s disease as an immunodeficiency

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

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