Perinparajah, Soumya;
(2023)
Mathematical Modelling of CD19 B Cell Reconstitution in Children After Insult to the Immune System.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
An insult to the immune system is followed by a period of immune reconstitution. During recovery, patients are immunocompromised and susceptible to infection, and routine blood tests are performed for clinical monitoring. Children display heterogeneity in their recovery from such insults due to ongoing development and maturation. Non-linear mixed effects (NLME) modelling is widely used to fit a model to observed data (e.g., repeated measurements of a biomarker) related to covariates. In addition, NLME models can be made mechanistic by incorporating prior knowledge to estimate biologically meaningful parameters. In this thesis, mechanistic NLME models were constructed to quantify B cell reconstitution in children after four insults to the immune system: haematopoietic stem cell transplantation (HSCT), rituximab therapy for Epstein-Barr virus (EBV) reactivation post-HSCT, viral dynamics of EBV reactivation and rituximab biosimilar therapy for rheumatological disease. A novel model of CD19+ cell reconstitution post-HSCT was first constructed. To scale CD19+ cell dynamics for age, prior biological knowledge was used to build a B cell maturation function. A Hill-type function was included to estimate the time delay between HSCT and bone marrow output of CD19+ cells. The drug effect of rituximab was then incorporated to create a kinetic pharmacodynamic (K-PD) model to identify the pharmacodynamics of rituximab on B cell reconstitution post-HSCT in patients with EBV reactivation. In addition, a simplified version of the K-PD model was used to identify the pharmacodynamics of rituximab biosimilars on B cells. Finally, a modified version of a published human immunodeficiency virus (HIV) model was integrated with the rituximab K-PD model to create a new model quantifying the viral dynamics of EBV reactivation. Other analyses included developing a Cox proportional hazards model for time to first EBV reactivation event post-HSCT and sensitivity analysis of a previously reported EBV model.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Mathematical Modelling of CD19 B Cell Reconstitution in Children After Insult to the Immune System |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10178376 |
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