- Author
-
S.M.P.D. Keizer
- Title
- Complement activation defects in pediatric oncology patients
- Subtitle
- Hidden factors contributing to the increased risk of infection
- Supervisors
-
T.W. Kuijpers
- Co-supervisors
-
D. Wouters
M.D. van de Wetering - Award date
- 18 May 2018
- Number of pages
- 213
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Infection is the most important cause of treatment-related deaths in oncology and the second most common reason for hospitalization during therapy. The risk of infection and inflammation is increased due to treatment-induced neutropenia, making them more dependent on their non-cellular immunity – the complement system, which consists of the classic, alternative and lectin route of complement activation.
The dependence on innate host defense mechanisms might be more prominent in children because of the relative immaturity of the immune system. The identification of specific risk factors for infection could improve patient care. The focus of this study was therefore on the functionality of the complement system during oncological treatment in pediatric oncology patients.
Using a longitudinal, prospective observation study we were able to show that pediatric oncology patients suffer from transient therapy-induced complement defects in one or more activation routes. Some these observed complement defects were associated to specific therapies or compounds, but the precise mechanisms have yet to be elucidated. We were able to show that Asparaginase is able to directly interact with the functionality of the lectin pathway of complement, independent of protein synthesis.
The lectin pathway is one of the three activation pathways of the complement system and reduced activation of this route has been associated with an increased risk of infection in immunocompromised patients. MBL-deficiency is common and reconstitution with plasma-derived MBL has been used to restore the lectin pathway functionality, albeit with limited effect. Analysis of the characteristics of plasma-derived MBL following substitution showed the rapid inactivation of the product by the natural inhibitor, C1-inhibitor. These newly formed inactivated complexes are rapidly cleared from the bloodstream. Substitution using recombinant MBL could provide a more efficacious therapeutic intervention. - Persistent Identifier
- https://hdl.handle.net/11245.1/6d7d7c57-e1bc-44aa-a760-133e9bf1660f
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