Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

Boot, Rolf G.; Verhoek, Marri; Fost, Maaike de; Hollak, Carla E. M.; Maas, Mario; Bleijlevens, Boris; Breemen, Mariëlle J. van; Meurs, Marjan van; Boven, Leonie A.; Laman, Jon D.; Moran, Mary Teresa; Cox, Timothy M.; Aerts, Johannes M. F. G.

doi:10.1182/blood-2003-05-1612

Cited by 294 publications

(222 citation statements)

References 34 publications

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“…The median values were clearly elevated compared with values reported for healthy controls or asymptomatic glucocerebrosidase-deficient patients; since Gaucher cells secrete chitotriosidase and the chemokine CCL18 [18,19], these results may indicate that there may be significant glucosylceramide storage even after 2 or more years of previous imiglucerase treatment, and even though chitotriosidase is not glucosylceramide storage-specific.…”

Section: Discussionmentioning

confidence: 51%

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

et al. 2015

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Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirtyeight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10-50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 3 10 9 /L at baseline, were given at least one 15 U/kg-dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for antiimiglucerase antibodies at baseline. This patient tested positive for anti-velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes.

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Section: Discussionmentioning

confidence: 51%

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

et al. 2015

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“…The CC-Chemokine CCL18, previously named ''pulmonary and activation-regulated chemokine'' is strongly expressed in human lungs and less in other lymphatic tissue like lymph nodes or thymus. CCL18, which is constantly present in the serum of healthy subjects, has no counterpart in rodents and its serum level is increased in several benign and malign diseases like lung fibrosis, atopic dermatitis, Gaucher disease, and leukemia [10][11][12][13]. Some authors also demonstrate that the level of CCL18 is elevated in body fluids and serum of patients with ovarian carcinoma [14,15].…”

Section: Introductionmentioning

confidence: 82%

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

et al. 2012

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CC-chemokine ligand18 (CCL18) ismainly expressed by alternativelyactivated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlatedthese data with histology, tumor stage and clinicalparameters. Mean CCL18 serum levelofthe patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vssquamous cell carcinoma 187(857) ng/ml, p,0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p,0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p,0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p,0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p,0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.

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“…For instance, it is noteworthy that both CHIT1 and CCL18 have proved to be extremely useful serum markers for Gaucher disease. 41 How can the identification of M2 activation profiles be reconciled with previous reports detailing elevated levels of pro-inflammatory (M1) macrophage markers in the periprosthetic tissues of osteolysis patients? One possibility is that proinflammatory responses to wear may be transient in nature, being supplanted by M2 responses during granuloma development and fibrosis in the later stages of disease represented by the revision surgery patients included in our study.…”

Section: Discussionmentioning

confidence: 97%

“…34 Recently, it has been shown that Gaucher cells, macrophagelike cells present in individuals with the lysosomal storage disorder Gaucher disease, demonstrate a phenotype reminiscent of alternatively activated macrophages characterized by elevated levels of markers such as CHIT1 and CCL18, but not pro-inflammatory mediators. 41,42 Because we had detected no significant increases in TNF-a or IL-6 in our osteolysis patients, we investigated the possibility that macrophages in osteolysis patients may also demonstrate indications of an alternatively activated phenotype. Remarkably, expression profiling revealed dramatic increases in expression of both CHIT1 and CCL18 in the periprosthetic tissues of osteolysis patients.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Koulouvaris

Ivashkiv

et al. 2007

Journal Orthopaedic Research

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Interactions between periprosthetic cells and prosthetic wear debris have been recognized as an important event in the development of osteolysis and aseptic loosening. Although the ability of wear debris to activate pro-inflammatory macrophage signaling has been documented, the full repertoire of macrophage responses to wear particles has not been established. Here, we examined the involvement of alternative macrophage activation and defective osteogenic signaling in osteolysis. Using real-time RT-PCR analysis of periprosthetic soft tissue from osteolysis patients, we detected elevated levels of expression of alternative macrophage activation markers (CHIT1, CCL18), chemokines (IL8, MIP1 a) and markers of osteoclast precursor cell differentiation and multinucleation (Cathepsin K, TRAP, DC-STAMP) relative to osteoarthritis controls. The presence of cathepsin K positive multinuclear cells was confirmed by immunohistochemistry. Reduced expression levels of the osteogenic signaling components BMP4 and FGF18 were detected. Expression levels of TNF-a, IL-6, and RANKL were unchanged, while the anti-osteoclastogenic cytokine OPG was reduced in osteolysis patients, resulting in elevated RANKL:OPG ratios. In vitro studies confirmed the role of particulate debris in alternative macrophage activation and inhibition of osteogenic signaling. Taken together, these results suggest involvement in osteolysis of alternative macrophage activation, accompanied by elevated levels of various chemokines. Increased recruitment and maturation of osteoclast precursors is also observed, as is reduced osteogenesis. These findings provide new insights into the molecular pathogenesis of osteolysis, and identify new potential candidate markers for disease progression and therapeutic targeting. ß

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Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

Cited by 294 publications

References 34 publications

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease

Serum Level of CC-Chemokine Ligand 18 is Increased in Patients with Non-small-cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

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