Mathematical modeling of endogenous and exogenously administered T cell recirculation in mouse and its application to pharmacokinetic studies of cell therapies.
Front Immunol
; 15: 1357706, 2024.
Article
in En
| MEDLINE
| ID: mdl-38846946
ABSTRACT
Introduction:
In vivo T cell migration has been of interest to scientists for the past 60 years. T cell kinetics are important in the understanding of the immune response to infectious agents. More recently, adoptive T cell therapies have proven to be a most promising approach to treating a wide range of diseases, including autoimmune and cancer diseases, whereby the characterization of cellular kinetics represents an important step towards the prediction of therapeutic efficacy.Methods:
Here, we developed a physiologically-based pharmacokinetic (PBPK) model that describes endogenous T cell homeostasis and the kinetics of exogenously administered T cells in mouse. Parameter calibration was performed using a nonlinear fixed-effects modeling approach based on published data on T cell kinetics and steady-state levels in different tissues of mice. The Partial Rank Correlation Coefficient (PRCC) method was used to perform a global sensitivity assessment. To estimate the impact of kinetic parameters on exogenously administered T cell dynamics, a local sensitivity analysis was conducted.Results:
We simulated the model to analyze cellular kinetics following various T cell doses and frequencies of CCR7+ T cells in the population of infused lymphocytes. The model predicted the effects of T cell numbers and of population composition of infused T cells on the resultant concentration of T cells in various organs. For example, a higher percentage of CCR7+ T cells among exogenously administered T lymphocytes led to an augmented accumulation of T cells in the spleen. The model predicted a linear dependence of T cell dynamics on the dose of adoptively transferred T cells.Discussion:
The mathematical model of T cell migration presented here can be integrated into a multi-scale model of the immune system and be used in a preclinical setting for predicting the distribution of genetically modified T lymphocytes in various organs, following adoptive T cell therapies.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes
Limits:
Animals
Language:
En
Journal:
Front Immunol
Year:
2024
Document type:
Article
Affiliation country:
RUSSIA
Country of publication:
Switzerland