An integrative physiologically-based model of T lymphocyte homeostasis and exogenously administered T cell kinetics
Antonina Nikitich (1, 3), Kirill Peskov (1, 2, 3), Gabriel Helmlinger (4), Gennady Bocharov (3, 5, 6)
(1) Research Centre for Model-Informed Drug Development, I.M. Sechenov First Moscow State Medical University, Moscow, Russia, (2) Modeling and Simulation Decisions FZ - LLC, Dubai, UAE, (3) Marchuk Institute of Numerical Mathematics RAS, Moscow, Russia, (4) Biorchestra Co., Ltd., Cambridge, MA, USA (5) Institute for Computer Science and Mathematical Modelling, I.M. Sechenov First Moscow State Medical University, Moscow, Russia (6) Moscow Center of Fundamental and Applied Mathematics at INM RAS, Moscow, Russia
Objectives: Processes related to the migration and circulation of lymphocytes are critical for the functioning of the immune system and have been extensively studied over the past 60 years. Nonclinical studies have been mostly conducted in experimental murine models, starting from the administration of lymphocytes to the thoracic duct, to studies today administering CAR-T and other T cell products engineered ex vivo. A detailed, quantitative understanding of T cell trafficking processes and resultant tissue distribution is therefore essential, from both a fundamental immunology perspective and a practical standpoint, specifically to support strategies and decision-making in the development of novel engineered T cell therapies. The objective of the present study was to develop a physiologically-based model describing trafficking patterns of endogenous T cells under homeostatic conditions and the kinetics of exogenously administered T cells upon intravenous (IV) infusion, all based on experimental data available in the literature.
Methods: A systematic review of published data on T cell trafficking in mouse was conducted. Experimental data relevant for model development and validation were digitized and curated. Parameter calibration was performed using a nonlinear fixed-effect modeling approach. A Partial Rank Correlation Coefficient (PRCC) method was used to perform a global sensitivity analysis of the model. To estimate the impact of kinetic parameters on exogenously administered T cell dynamics, a local sensitivity analysis was conducted. Model development and analyses were performed in the Monolix 2020 software (Monolix documentation - LIXOFT, www.monolix.lixoft.com) and R Statistics software, version 4.0.2.
Results: The model was formulated as a system of ordinary differential equations describing multi-compartmental processes of T cell trafficking in the organism; exclusive trafficking of CCR7+ T cells to lymph nodes (LNs) was explicitly included. The model consistently described the experimental data [1-3], including the accumulation of endogenous T cells in lymphoid organs, at concentrations of ~1.57*108 cells/ml in the spleen and ~3.36*108 cells/ml in LNs, and steady-state levels of T cells in blood, lungs and liver (respectively, ~1.70*106 cells/ml, ~4.22*106 cells/ml, and ~4.20*105 cells/ml). The most significant processes contributing to homeostatic levels of T cells were the inflow rate of T cells from the thymus to blood, the apoptosis of T cells, and homeostatic T cell proliferation in spleen. The model adequately reproduced data on exogenously administered T cell kinetics [4], including the rapid T cell elimination process from blood and infiltration into the lungs, as well as the slower cell kinetics in the spleen (Cmax of ~12.6*106 cells/ml at 9 hrs) and the liver (Cmax of ~3.4*106 cells/ml at 8.0 hrs) where Cmax stands for the maximum concentration of T cells. It also satisfactorily described the cellular kinetics in the regional LN compartment, with a Cmax of ~0.5*106 cells/ml at 45.5 hrs post IV administration. Model simulations showed a linear dose-concentration dependence, in accordance with experimental data [5]. Simulations of an IV administration scenario with a higher portion of CCR7+ T cells resulted in higher T cell exposure with a relatively increased accumulation in the spleen and blood.
Conclusions: The proposed physiologically-based model adequately described the homeostatic recirculation patterns of endogenous T cells and the kinetics of exogenously administered T cells upon an IV infusion. It was used to perform predictive simulations of distribution patterns of genetically-modified T lymphocyte levels in various organs, following the adoptive administration of T cells.
References:
[1] Boyer et al. Clonal and Quantitative In Vivo Assessment of Hematopoietic Stem Cell Differentiation Reveals Strong Erythroid Potential of Multipotent Cells. Stem Cell Reports 2019 Apr 9;12(4):801-815
[2] Mitsumi et al, T cells protect against hepatitis A Virus Infection and Limit Infection-Induced Liver Injury. J Hepatol 2021 Dec;75(6):1323-1334
[3] Cosgrove J, Hustin LSP, de Boer RJ, Perié L. Hematopoiesis in Numbers. Trends Immunol. 2021 Dec;42(12):1100–12
[4] Khot et al. Measurement and Quantitative Characterization of Whole-Body Pharmacokinetics of Exogenously Administered T Cells in Mice, J Pharmacol Exp Ther 368:503–513, March 2019
[5] Zatz MM, Lance EM. The Distribution of 51Cr-Labeled Lymphocytes into Antigen-Stimulated Mice. J Exp Med. 1971 Jul 1;134(1):224–41
