Mannose-binding lectin (MBL) substitution: recovery of opsonic function in vivo lags behind MBL serum levels.
Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immunocompromised patients. MBL substitution in these patients might diminish these risks. We therefore performed an open, uncontrolled safety and pharmacokinetic MBL-substitution study in 12 pediatric oncology patients with chemotherapy-induced neutropenia. Twice weekly MBL infusions with plasma-derived MBL yielded MBL trough levels >1.0 microg/ml. We tested whether MBL substitution in vivo increased MBL-dependent complement activation and opsonophagocytosis of zymosan in vitro. Upon MBL substitution, opsonophagocytosis by control neutrophils increased significantly (p < 0.001) but remained suboptimal, although repeated MBL infusions resulted in improvement over time. The MBL-dependent MBL-associated serine protease (MASP)-mediated complement C3 and C4 activation also showed a suboptimal increase. To explain these results, complement activation was studied in detail. We found that in the presence of normal MASP-2 blood levels, MASP-2 activity (p < 0.0001) was reduced as well as the alternative pathway of complement activation (p < 0.05). This MBL-substitution study demonstrates that plasma-derived MBL infusions increase MBL/MASP-mediated C3 and C4 activation and opsonophagocytosis, but that higher circulating levels of plasma-derived MBL are required to achieve MBL-mediated complement activation comparable to healthy controls. Other patient cohorts should be considered to demonstrate clinical efficacy in phase II/III MBL-substitution studies, because we found a suboptimal recovery of (in vitro) biological activity upon MBL substitution in our neutropenic pediatric oncology cohort.
Brouwer
Nannette
N
Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. n.brouwer@mca.nl
Frakking
Florine N J
FN
van de Wetering
Marianne D
MD
van Houdt
Michel
M
Hart
Margreet
M
Budde
Ilona Kleine
IK
Strengers
Paul F W
PF
Laursen
Inga
I
Houen
Gunnar
G
Roos
Dirk
D
Jensenius
Jens C
JC
Caron
Huib N
HN
Dolman
Koert M
KM
Kuijpers
Taco W
TW
D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003167:Complement Activation / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D037601:Mannose-Binding Lectin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000235:genetics*; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D009895:Opsonin Proteins / Q000097:blood / Q000502:physiology*; D010587:Phagocytosis / Q000276:immunology; D011446:Prospective Studies
D037601:Mannose-Binding Lectin; D009895:Opsonin Proteins; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases