Impact of immunosuppressive therapy on brain derived cytokines after liver transplantation.
Aged
Brain
/ metabolism
Brain-Derived Neurotrophic Factor
/ blood
Calcineurin Inhibitors
/ adverse effects
Cell Self Renewal
Cohort Studies
Female
Gene Expression Regulation
Humans
Immunosuppression Therapy
Interferon-gamma
/ blood
Liver Transplantation
Male
Middle Aged
Neuroimmunomodulation
/ drug effects
Neuronal Plasticity
Platelet-Derived Growth Factor
/ metabolism
T-Lymphocytes
/ metabolism
Brain
Brain derived cytokines
Cognitive function
Imaging
Immunosuppression
Journal
Transplant immunology
ISSN: 1878-5492
Titre abrégé: Transpl Immunol
Pays: Netherlands
ID NLM: 9309923
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
20
05
2019
accepted:
27
09
2019
pubmed:
2
11
2019
medline:
1
4
2021
entrez:
1
11
2019
Statut:
ppublish
Résumé
While acute neurotoxic side effects of calcineurin inhibitors (CNI) are well-known, data upon long-term effects on brain structure and function are sparse. We hypothesize that long-term CNI therapy affects the neuroimmune system, thereby, increasing the risk of neurodegeneration. Here, we measured the impact of CNI therapy on plasma levels of brain- and T cell-derived cytokines in a cohort of patients after liver transplantation (LT). Levels of T cell-mediated cytokines (e.g. Interferon-γ (IFN-γ)) and brain-derived cytokines (e.g. brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF)) were measured by multiplex assays in plasma of 82 patients about 10 years after LT (17 with CNI free, 35 with CNI low dose, 30 with standard dose CNI immunosuppression) and 33 healthy controls. Data were related to psychometric test results and parameters of cerebral magnetic resonance imaging. IFN-γ levels were significantly higher in the CNI free LT patient group (p=0.027) compared to healthy controls. BDNF levels were significantly lower in LT patients treated with CNI (CNI low: p<0.001; CNI standard: p=0.016) compared to controls. PDGF levels were significantly lower in the CNI low dose group (p=0.004) and for PDGF-AB/BB also in the CNI standard dose group (p=0.029) compared to controls. BDNF and PDGF negatively correlated with cognitive function and brain volume (p<0.05) in the CNI low dose group. Our results imply that long-term treatment with CNI suppresses BDNF and PDGF expression, both crucial for neuronal signaling, cell survival and synaptic plasticity and thereby may lead to cognitive dysfunction and neurodegeneration.
Sections du résumé
BACKGROUND
While acute neurotoxic side effects of calcineurin inhibitors (CNI) are well-known, data upon long-term effects on brain structure and function are sparse. We hypothesize that long-term CNI therapy affects the neuroimmune system, thereby, increasing the risk of neurodegeneration. Here, we measured the impact of CNI therapy on plasma levels of brain- and T cell-derived cytokines in a cohort of patients after liver transplantation (LT).
METHODS
Levels of T cell-mediated cytokines (e.g. Interferon-γ (IFN-γ)) and brain-derived cytokines (e.g. brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF)) were measured by multiplex assays in plasma of 82 patients about 10 years after LT (17 with CNI free, 35 with CNI low dose, 30 with standard dose CNI immunosuppression) and 33 healthy controls. Data were related to psychometric test results and parameters of cerebral magnetic resonance imaging.
RESULTS
IFN-γ levels were significantly higher in the CNI free LT patient group (p=0.027) compared to healthy controls. BDNF levels were significantly lower in LT patients treated with CNI (CNI low: p<0.001; CNI standard: p=0.016) compared to controls. PDGF levels were significantly lower in the CNI low dose group (p=0.004) and for PDGF-AB/BB also in the CNI standard dose group (p=0.029) compared to controls. BDNF and PDGF negatively correlated with cognitive function and brain volume (p<0.05) in the CNI low dose group.
CONCLUSION
Our results imply that long-term treatment with CNI suppresses BDNF and PDGF expression, both crucial for neuronal signaling, cell survival and synaptic plasticity and thereby may lead to cognitive dysfunction and neurodegeneration.
Identifiants
pubmed: 31669260
pii: S0966-3274(19)30066-8
doi: 10.1016/j.trim.2019.101248
pii:
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Calcineurin Inhibitors
0
Platelet-Derived Growth Factor
0
platelet-derived growth factor A
0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101248Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.