2013 - Glasgow - Scotland

PAGE 2013: Drug/Disease modelling
Rollo Hoare

A Novel Mechanistic Model for CD4 Lymphocyte Reconstitution Following Paediatric Haematopoietic Stem Cell Transplantation

Rollo L Hoare (1,2), Robin Callard (1,2), Paul Veys (1,3), Nigel Klein (1,3), Joseph F Standing (1,2,3)

(1) Institute of Child Health, University College London, 30 Guilford St, London, UK; (2) Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, Gower St, London, UK; (3) Great Ormond Street Hospital NHS Foundation Trust, Great Ormond St, London, UK

Objectives: Before a haematopoietic stem cell transplant (HSCT), a child will usually be given a conditioning regimen to reduce or ablate the host immune system in order to prevent graft rejection. Following HSCT, long-term successful outcomes and short-term complications are associated with the rate and extent of recovery in the child's immune system. Studying immune reconstitution in children presents a huge challenge as the rapidly developing immune system means that expected CD4 T cell counts (a key subset of lymphocytes) for age can vary by as much as three-fold [1]. This work presents a new mechanistic model that has been developed which describes the reconstitution of total body CD4 T cell count with time in children who have had an HSCT.

Methods: The fundamental model of the CD4 cell count has three parameters representing, the initial total body CD4 cell count, thymic output of CD4 cells, and the net loss rate of CD4 cells. The model is made more mechanistic in three ways: (1) accounting for age-related changes in the thymus with a functional form for thymic output [2]; (2) allowing for thymic output not recovering production immediately after the HSCT; (3) including the effects of competition for homeostatic signals leading to changes in the net loss rate with cell quantities. We apply this model to longitudinal data collected in the bone marrow transplant unit in Great Ormond Street Hospital.

Results: Adding the effects of reduced thymic function and competition both significantly improved model fit, and the final model had good descriptive and simulation properties.  In the long term, the modelled population average returned to, or very near to, the total body CD4 count expected for a healthy child. The dynamics of the thymus returning to full production agree well with experimental evidence [3].

Conclusions: A novel mechanistic model for the immune reconstitution of CD4 cells after HSCTs in children has been developed. The model brings together many ideas about the immune system in children, including the changes in the thymus with age, and appears to show clearly the necessity of including both the effects of reduced thymic function post HSCT, and of competition for homeostatic signals by CD4 cells in the body. It is now possible to carry out a multivariate analysis and find which parts of the immune system are affected by covariates such as disease type, drug pre-conditioning, and graft-versus-host disease prophylaxis.

[1] S Huenecke et al. Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis. Eur J Haematol 2008; 80(6): 532-39
[2] I Bains et al. Quantifying thymic export: combining models of naive T cell proliferation and TCR excision circle dynamics gives an explicit measure of thymic output. J Immunol 2009; 183: 4329-36
[3] PR Fallen et al. Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients. Bone Marrow Transplant 2003; 32: 1001-14

Reference: PAGE 22 (2013) Abstr 2676 [www.page-meeting.org/?abstract=2676]
Oral: Drug/Disease modelling
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