TY - JOUR
T1 - Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels
AU - Brouwer, Nannette
AU - Frakking, Florine N. J.
AU - van de Wetering, Marianne D.
AU - van Houdt, Michel
AU - Hart, Margreet
AU - Budde, Ilona Kleine
AU - Strengers, Paul F. W.
AU - Laursen, Inga
AU - Houen, Gunnar
AU - Roos, Dirk
AU - Jensenius, Jens C.
AU - Caron, Huib N.
AU - Dolman, Koert M.
AU - Kuijpers, Taco W.
PY - 2009
Y1 - 2009
N2 - Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immuno-compromised 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 mu g/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. The Journal of Immunology, 2009, 183: 3496-3504
AB - Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immuno-compromised 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 mu g/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. The Journal of Immunology, 2009, 183: 3496-3504
U2 - https://doi.org/10.4049/jimmunol.0900445
DO - https://doi.org/10.4049/jimmunol.0900445
M3 - Article
C2 - 19657091
SN - 0022-1767
VL - 183
SP - 3496
EP - 3504
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 5
ER -