Dynamics of Inflammatory and Neurodegenerative Biomarkers after Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

Abstract

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or enhances beneficial processes in MS. The disease pathomechanisms include neuroinflammation, glial cell activation and neuronal damage. We studied biomarkers that in part reflect these, like markers for neuroinflammation (C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL13, and chitinase 3-like 1 (CHI3L1)), glial perturbations (glial fibrillary acidic protein (GFAP) and in part CHI3L1), and neurodegeneration (neurofilament light chain (NfL)) by enzyme-linked immunosorbent assays (ELISA) and single-molecule array assay (SIMOA) in the serum and cerebrospinal fluid (CSF) of 32 MS patients that underwent aHSCT. We sampled before and at 1, 3, 6, 12, 24 and 36 months after aHSCT for serum, as well as before and 24 months after aHSCT for CSF. We found a strong increase of serum CXCL10, NfL and GFAP one month after the transplantation, which normalized one and two years post-aHSCT. CXCL10 was particularly increased in patients that experienced reactivation of cytomegalovirus (CMV) infection, but not those with Epstein-Barr virus (EBV) reactivation. Furthermore, patients with CMV reactivation showed increased Th1 phenotype in effector memory CD4+ T cells. Changes of the other serum markers were more subtle with a trend for an increase in serum CXCL9 early post-aHSCT. In CSF, GFAP levels were increased 24 months after aHSCT, which may indicate sustained astroglia activation 24 months post-aHSCT. Other CSF markers remained largely stable. We conclude that MS-related biomarkers indicate neurotoxicity early after aHSCT that normalizes after one year while astrocyte activation appears increased beyond that, and increased serum CXCL10 likely does not reflect inflammation within the central nervous system (CNS) but rather occurs in the context of CMV reactivation or other infections post-aHSCT.

CSF Concentrations of CXCL13 and sCD27 Before and After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis

“…The most likely explanation for this is that most of the patients were heavily pretreated with B-cell–depleting agents, such as rituximab and ocrelizumab. 24 In this study, in which the patients received more various DMDs before AHSCT, patients treated with second-line DMDs had much lower CSF concentrations of CXCL13 at baseline. This reinforces the idea that CXCL13 reflects acute inflammation.…”

“…In a previous study, CSF CXCL13 was measured before and after AHSCT with an intermediate conditioning regimen. 24 The follow-up was relatively short (1 year), the number of investigated patients was few, and the patients came from a mixed population of patients with RRMS and patients with progressive disease. Although they used the same assay as in our study, they failed to detect CXCL13 in the samples.…”

Development of a new HISCL automated CXCL9 immunoassay

“…Notably, serum CXCL9 levels in all HCs were above this LoQ, indicating that this reagent is sufficiently sensitive for measuring serum samples. This LoQ is lower than that of the current commercial immune ELISA system 14 . According to a previous report, the CXCL9 level in bronchoalveolar lavage fluid collected from patients with ILD was > 1 pg/mL, with some samples below the quantification range 5 .…”

Dynamics of T cell repertoire renewal following autologous hematopoietic stem cell transplantation in multiple sclerosis

“…Immune renewal declines above 50 years ( 90 ), and therefore, this age is considered the upper limit for aHSCT in MS. Our results indicate more rapid immune reconstitution in younger individuals and women, which is consistent with favorable clinical results in younger individuals with aggressive relapsing-remitting disease ( 91 ). CMV reactivation may suppress thymic activity and hinder particularly CD4 + T cell recovery after aHSCT ( 50 , 92 )( 93 ). Our data show delayed CD4 + and quick CD8 + T cell reconstitution, particularly for EM and TEMRA CD8 + T cells in patients with CMV reactivation.…”