Abstract
Objectives Autologous haematopoietic stem cell transplantation (AHSCT) is a vital therapeutic option for aggressive multiple sclerosis (MS). The mechanism by which AHSCT enables sustained remission beyond lymphopenia remains to be elucidated.
Methods Bio-banked lymphocytes were collected from MS patients enrolled in a phase 2 trial (ACTRN12613000339752), and comparator patients treated with Natalizumab. A multicolour flow cytometry panel was performed on 19 patient samples pre-AHSCT, 6, 12, 24 and 36 months post-AHSCT. DNA markers of thymic function were performed in the same cohort, and thymic PET studies in three patients. Fluorescence-activated cell-sorted T cell sub-populations were acquired for mRNA T-cell receptor sequencing in 13 patients.
Results Early proliferation of (effector and terminal effector) memory T-cells is followed by delayed recovery of naive CD4+ lymphocytes. 40.8% (CD4+CD45RO+) and 32.8% (CD8+CD45RO+) of clones from the pre-transplant repertoire were detected at 6 months, yet only 19% (CD4+; p<0.025) and 13% (CD8+; p<0.005) of pre-transplant clones were detected at 36 months. Diversity of the memory populations declined post-transplant (p = 0.012). Recovery of a thymically-derived naïve T cell repertoire is ongoing at 36 months, however diversity of the naïve populations only increased from baseline in responders, with activity correlated on PET imaging. In HLA-DRB1*15:01-positive patients, public clones are probed as biomarkers of disease. Twelve public CD4+ clones correlate with disease activity, and two display characteristics on GLIPH2 analysis of autoreactivity.
Conclusions AHSCT induces sustained remission with dynamic changes in clonal T cell repertoire out to 36 months post-transplant, including the deletion of putative auto-reactive clones.
