Reduced microglia activity in patients with long-term immunosuppressive therapy after liver transplantation

Abstract

Purpose Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. Methods PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. Results In controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. Conclusion Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

How calcineurin inhibitors affect cognition

“…In patients who had had chronic immunosuppressive therapy following liver transplantation, CNI treatment was associated with suppression of microglial activity. 78 Although the phagocytosis of Aβ by microglia may produce therapeutic benefits, persistent stimulation of microglia by Aβ can have negative consequences and lead to prolonged inflammation. 79 Moreover, the deactivation of NFATs by CNI affected various cellular pathways in glial cells, namely glutamate uptake and cytokine signaling.…”

“…It is important to document that 77.8% of enrolled patients were aged less than 65 years, representing a low probability of developing neurocognitive disorders. In patients who had had chronic immunosuppressive therapy following liver transplantation, CNI treatment was associated with suppression of microglial activity 78 . Although the phagocytosis of Aβ by microglia may produce therapeutic benefits, persistent stimulation of microglia by Aβ can have negative consequences and lead to prolonged inflammation 79 .…”

Imaging translocator protein expression with positron emission tomography

“…Finally, we have included several articles that are nonbrain TSPO studies as there has been a recent surge to use TSPO radiotracers for imaging of pathologies in organs besides the brain, which poses different problems compared to brain imaging, such as radiotracer metabolites entering the tissue. This series includes original contributions at a preclinical level, with validation of a simplified quantification method for novel TSPO tracer, [ 18 F]-LW223, in rat heart and brain for future whole body PET studies [21] as well as clinical studies for head and neck cancer with [ 18 F]F-DPA-714 [22], and after liver transplant with [ 18 F]GE-180 [23].…”