Cargando…
Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site
Introduction: The adoptive transfer of regulatory T cells (Tregs) has emerged as a method to promote graft tolerance. Clinical trials have demonstrated the safety of adoptive transfer and are now assessing their therapeutic efficacy. Strategies that generate large numbers of antigen specific Tregs a...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035492/ https://www.ncbi.nlm.nih.gov/pubmed/35479106 http://dx.doi.org/10.3389/ti.2022.10297 |
_version_ | 1784693303264935936 |
---|---|
author | Lapp, Maya M. Lin, Guang Komin, Alexander Andrews, Leah Knudson, Mei Mossman, Lauren Raimondi, Giorgio Arciero, Julia C. |
author_facet | Lapp, Maya M. Lin, Guang Komin, Alexander Andrews, Leah Knudson, Mei Mossman, Lauren Raimondi, Giorgio Arciero, Julia C. |
author_sort | Lapp, Maya M. |
collection | PubMed |
description | Introduction: The adoptive transfer of regulatory T cells (Tregs) has emerged as a method to promote graft tolerance. Clinical trials have demonstrated the safety of adoptive transfer and are now assessing their therapeutic efficacy. Strategies that generate large numbers of antigen specific Tregs are even more efficacious. However, the combinations of factors that influence the outcome of adoptive transfer are too numerous to be tested experimentally. Here, mathematical modeling is used to predict the most impactful treatment scenarios. Methods: We adapted our mathematical model of murine heart transplant rejection to simulate Treg adoptive transfer and to correlate therapeutic efficacy with Treg dose and timing, frequency of administration, and distribution of injected cells. Results: The model predicts that Tregs directly accumulating to the graft are more protective than Tregs localizing to draining lymph nodes. Inhibiting antigen-presenting cell maturation and effector functions at the graft site was more effective at modulating rejection than inhibition of T cell activation in lymphoid tissues. These complex dynamics define non-intuitive relationships between graft survival and timing and frequency of adoptive transfer. Conclusion: This work provides the framework for better understanding the impact of Treg adoptive transfer and will guide experimental design to improve interventions. |
format | Online Article Text |
id | pubmed-9035492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90354922022-04-26 Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site Lapp, Maya M. Lin, Guang Komin, Alexander Andrews, Leah Knudson, Mei Mossman, Lauren Raimondi, Giorgio Arciero, Julia C. Transpl Int Health Archive Introduction: The adoptive transfer of regulatory T cells (Tregs) has emerged as a method to promote graft tolerance. Clinical trials have demonstrated the safety of adoptive transfer and are now assessing their therapeutic efficacy. Strategies that generate large numbers of antigen specific Tregs are even more efficacious. However, the combinations of factors that influence the outcome of adoptive transfer are too numerous to be tested experimentally. Here, mathematical modeling is used to predict the most impactful treatment scenarios. Methods: We adapted our mathematical model of murine heart transplant rejection to simulate Treg adoptive transfer and to correlate therapeutic efficacy with Treg dose and timing, frequency of administration, and distribution of injected cells. Results: The model predicts that Tregs directly accumulating to the graft are more protective than Tregs localizing to draining lymph nodes. Inhibiting antigen-presenting cell maturation and effector functions at the graft site was more effective at modulating rejection than inhibition of T cell activation in lymphoid tissues. These complex dynamics define non-intuitive relationships between graft survival and timing and frequency of adoptive transfer. Conclusion: This work provides the framework for better understanding the impact of Treg adoptive transfer and will guide experimental design to improve interventions. Frontiers Media S.A. 2022-04-11 /pmc/articles/PMC9035492/ /pubmed/35479106 http://dx.doi.org/10.3389/ti.2022.10297 Text en Copyright © 2022 Lapp, Lin, Komin, Andrews, Knudson, Mossman, Raimondi and Arciero. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Health Archive Lapp, Maya M. Lin, Guang Komin, Alexander Andrews, Leah Knudson, Mei Mossman, Lauren Raimondi, Giorgio Arciero, Julia C. Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title | Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title_full | Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title_fullStr | Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title_full_unstemmed | Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title_short | Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site |
title_sort | modeling the potential of treg-based therapies for transplant rejection: effect of dose, timing, and accumulation site |
topic | Health Archive |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035492/ https://www.ncbi.nlm.nih.gov/pubmed/35479106 http://dx.doi.org/10.3389/ti.2022.10297 |
work_keys_str_mv | AT lappmayam modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT linguang modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT kominalexander modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT andrewsleah modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT knudsonmei modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT mossmanlauren modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT raimondigiorgio modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite AT arcierojuliac modelingthepotentialoftregbasedtherapiesfortransplantrejectioneffectofdosetimingandaccumulationsite |