An integrative mechanistic model of thymocyte dynamics

Front Immunol. 2024 Feb 26:15:1321309. doi: 10.3389/fimmu.2024.1321309. eCollection 2024.

Abstract

Background: The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases.

Methods: We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment.

Results: We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output.

Conclusions: In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.

Keywords: immune system; mechanistic model; thymic involution; thymopoiesis; thymus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Fingolimod Hydrochloride / metabolism
  • Fingolimod Hydrochloride / pharmacology
  • Fingolimod Hydrochloride / therapeutic use
  • Humans
  • Mice
  • Multiple Sclerosis* / metabolism
  • Thymocytes* / metabolism
  • Thymus Gland

Substances

  • Fingolimod Hydrochloride

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Academic leadership program Priority 2030 proposed by the Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), the Ministry of Science and Higher Education of the Russian Federation (Agreement 075-10-2021-093, Project MMD-RND-2266) and Modeling & Simulation Decisions FZ - LLC, Dubai, UAE. GB was supported by the Moscow Center of Fundamental and Applied Mathematics (agreement with the Ministry of Education and Science of the Russian Federation No. 075-15-2022-286). VK and KP were supported by the Russian Science Foundation (Grant Number 23-71-10051).