Cognitive impairments correlate with increased central nervous system immune activation after allogeneic haematopoietic stem cell transplantation

Abstract

Murine studies indicate that, after allogeneic haematopoietic stem cell transplantation (aHSCT), donor-derived macrophages replace damaged microglia and alloreactive T-cells invade the central nervous system (CNS). The clinical relevance of this is unknown. We assessed CNS immune surveillance and metabolic activity involved in neuronal survival, in relation to fatigue and cognitive dysfunction in 25 long-term survivors after aHSCT. Patients with cognitive dysfunction exhibited increased proportions of activated T-cells and CD16 + NK-cells in the cerebrospinal fluid (CSF). Immune cell activation was paralleled with reduced levels of anti-inflammatory factors involved in T-cell suppression (transforming growth factor-β, programmed death ligand-1), NK-cell regulation (poliovirus receptor, nectin-2), and macrophage and microglia activation (CD200, chemokine [C-X3-C motif] ligand-1). Additionally, the CSF mRNA expression pattern was associated with neuroinflammation and oxidative stress. Furthermore, proteomic, and transcriptomic studies demonstrated decreased levels of neuroprotective factors, and an upregulation of apoptosis pathway genes. The kynurenine pathway of tryptophan metabolism was activated in the CNS of all aHSCT patients, resulting in accumulation of neurotoxic and pro-inflammatory metabolites. Cognitive decline and fatigue are overlooked but frequent complications of aHSCT. This study links post-transplant CNS inflammation and neurotoxicity to our previously reported hypoactivation in the prefrontal cortex during cognitive testing, suggesting novel treatment targets.A) The kynurenine pathway of tryptophan metabolism was activated in all aHSCT patients. The levels of KYN and 3-HK, that readily cross the BBB, were increased in both plasma and CSF, while QUIN, that do not cross the BBB, was exclusively elevated in CSF, suggesting intrathecal production in microglia. QUIN and 3-HK have documented neurotoxic properties and may contribute to an underlying neurotoxic environment after aHSCT. B-D) Activated T-cells and CD16 + NK-cells were increased in the CSF of aHSCT patients with fatigue (C, D), coupled with decreased amounts of immune regulatory (green and blue dots) and neurotrophic (grey dots) proteins in the subgroup with cognitive dysfunction (D). In contrast, patients with normal cognition (B, C) had increased levels of reparative and anti-inflammatory factors, possibly counteracting the toxic environment highlighted by the increased apoptosis activity and signs of ongoing neuroinflammation observed in the mRNA sequencing analysis.