Modeling rejection immunity

Abstract

BackgroundTransplantation is often the only way to treat a number of diseases leading to organ failure. To overcome rejection towards the transplanted organ (graft), immunosuppression therapies are used, which have considerable side-effects and expose patients to opportunistic infections. The development of a model to complement the physician’s experience in specifying therapeutic regimens is therefore desirable. The present work proposes an Ordinary Differential Equations model accounting for immune cell proliferation in response to the sudden entry of graft antigens, through different activation mechanisms. The model considers the effect of a single immunosuppressive medication (e.g. cyclosporine), subject to first-order linear kinetics and acting by modifying, in a saturable concentration-dependent fashion, the proliferation coefficient. The latter has been determined experimentally. All other model parameter values have been set so as to reproduce reported state variable time-courses, and to maintain consistency with one another and with the experimentally derived proliferation coefficient.ResultsThe proposed model substantially simplifies the chain of events potentially leading to organ rejection. It is however able to simulate quantitatively the time course of graft-related antigen and competent immunoreactive cell populations, showing the long-term alternative outcomes of rejection, tolerance or tolerance at a reduced functional tissue mass. In particular, the model shows that it may be difficult to attain tolerance at full tissue mass with acceptably low doses of a single immunosuppressant, in accord with clinical experience.ConclusionsThe introduced model is mathematically consistent with known physiology and can reproduce variations in immune status and allograft survival after transplantation. The model can be adapted to represent different therapeutic schemes and may offer useful indications for the optimization of therapy protocols in the transplanted patient.

Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site

“…We established one of the first theoretical models to describe the immune system and transplant dynamics that give rise to transplant rejection, and ours is currently the only transplantation model using differential equations to track Tregs independently from other T cell populations ( 30 ). Both our work and that of De Gaetano et al incorporated experimental methods in developing transplant rejection models ( 30 , 31 ). However, no mathematical model to date provides a robust mechanism for analysis of Treg adoptive transfer on the immune response to transplantation.…”

“…Mathematical and computational models have been widely used in conjunction with experimental methods in cancer and virology to understand immune system dynamics and aid in the design of effective immunotherapies ( 27 – 29 ), but their application in transplantation is lacking. Some theoretical models for solid organ transplant rejection have been proposed ( 30 – 35 ), several of which focused on the impact of immunosuppression only ( 31 , 33 – 35 ) and used simplified representations of immune components. We established one of the first theoretical models to describe the immune system and transplant dynamics that give rise to transplant rejection, and ours is currently the only transplantation model using differential equations to track Tregs independently from other T cell populations ( 30 ).…”

A case for the reuse and adaptation of mechanistic computational models to study transplant immunology

“…A different approach is a model in which each graft cell and immune cell is simulated and followed individually (ABM, agent‐based model) and that studies the nonlinear interactions of effector and regulatory immune responses as well as immunosuppression in the graft at the levels of individual cells . ODE models have also been employed to study the direct and indirect mechanisms of T cell activation during transplant, as well as the interplay between immunosuppression and effective immune system control of viral infections on renal transplant patients …”