Different dose-dependent correction of MIP-1beta and chitotriosidase during initial enzyme replacement therapy.
In tissue lesions of type I Gaucher patients, characteristic lipid-laden macrophages, 'Gaucher cells', are surrounded by inflammatory phagocytes. Gaucher cells secrete the elevated plasma chitotriosidase. The elevated plasma MIP-1beta in Gaucher patients stems from the phagocytes surrounding the Gaucher cells. Plasma chitotriosidase and MIP-1beta decrease upon successful enzyme replacement therapy (ERT) with mannose-terminated recombinant glucocerebrosidase (alglucerase). Previous histochemical analysis of Gaucher spleens revealed that Gaucher cells express little mannose receptor, in contrast to surrounding phagocytes. We therefore investigated the corrective effects of ERT on plasma MIP-1beta and chitotriosidase in more detail. We also compared effects of one year of treatment with a relatively low dose and a relatively high dose of ERT. A more rapid correction in plasma MIP-1beta, compared to chitotriosidase, was observed in most patients on low-dose ERT. Correction of plasma MIP-1beta and chitotriosidase levels was more pronounced in the higher-dosed patient group. Upon prolonged treatment, differences in the effects of enzyme dose were no longer significant. Normalization of plasma MIP-1beta and chitotriosidase levels was attained in the majority of patients. In conclusion, ERT with mannose-terminated gluocerebrosidase results in prominent corrections of plasma chitotriosidase, a marker of Gaucher cells, and in particular of plasma MIP-1beta, a marker of inflammatory phagocytes. The sharper response in plasma MIP-1beta to ERT is in line with the observation that especially phagocytes surrounding Gaucher cells express mannose-receptors.
van Breemen
M J
MJ
Department of Medical Biochemistry, K1-262, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands. m.j.vanbreemen@amc.uva.nl
de Fost
M
M
Maas
M
M
Wiersma
M G
MG
Hollak
C E M
CE
Poll
L W
LW
Vom Dahl
S
S
Boot
R G
RG
Aerts
J M F G
JM
D000293:Adolescent; D000368:Aged; D054407:Chemokine CCL4 / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology*; D005962:Glucosylceramidase / Q000008:administration & dosage / Q000627:therapeutic use; D006596:Hexosaminidases / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013156:Splenectomy
C066507:CCL4 protein, human; D054407:Chemokine CCL4; C070292:alglucerase; D006596:Hexosaminidases; C086400:chitotriosidase; D005962:Glucosylceramidase