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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900445v1 183/5/3496    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Brouwer, N. Articles by Kuijpers, T. W. PubMed PubMed Citation Articles by Brouwer, N. Articles by Kuijpers, T. W.

Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels¹

Nannette Brouwer^2,*, Florine N. J. Frakking, Marianne D. van de Wetering, Michel van Houdt^*, Margreet Hart^*, Ilona Kleine Budde, Paul F. W. Strengers, Inga Laursen, Gunnar Houen, Dirk Roos^*, Jens C. Jensenius^¶, Huib N. Caron, Koert M. Dolman^*, and Taco W. Kuijpers^*,

^* Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands; Medical Department, Sanquin Plasma Products, Amsterdam, The Netherlands; Statens Serum Institut, Copenhagen, Denmark; and ^¶ Department of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark

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 µg/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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Landsteiner Stichting voor Bloedtransfusie Research (LSBR no. 0207).

² Address correspondence and reprint requests to Dr. Nannette Brouwer, Medical Centre Alkmaar, Laboratory KCHI, Juliana van Stolberglaan 13, 1814 HB Alkmaar, The Netherlands. E-mail address: n.brouwer{at}mca.nl

³ Abbreviations used in this paper: MBL, mannose-binding lectin; AU, arbitrary unit; MASP, MBL-associated serine protease; SSI, Statens Serum Institute.

⁴ The online version of this article contains supplemental material.