Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation

Abstract

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission in multiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8(+)T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1(+)CD8(+)T-cells and of PD-1-expressing CD19(+) B-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation

“…As expected, monocytes and NK cells were proportionally more abundant than CD4 T cell and B cell populations. This probably reflects slower kinetics of CD4 T cell and B cell reconstitution in the periphery, as reported previously . Consistent with prior reports, reconstituting cells in circulating CD4 and CD8 T cell compartments reflected a bias towards memory phenotype cells with a skewed distribution favouring effector memory and late effector subtypes .…”

“…This probably reflects slower kinetics of CD4 T cell and B cell reconstitution in the periphery, as reported previously . Consistent with prior reports, reconstituting cells in circulating CD4 and CD8 T cell compartments reflected a bias towards memory phenotype cells with a skewed distribution favouring effector memory and late effector subtypes . The altered balance of memory/naive subtypes in total CD4 and CD8 T cell populations analysed by CyTOF was recapitulated in circulating CD25 + CD127 –/low CD4 T regs analysed by flow cytometry.…”

“…To our knowledge, this is the first analysis, in any disease setting, to use CyTOF for extensive multi‐parameter immunophenotyping of peripheral blood in patients treated with high‐dose immunosuppressive therapy followed by autologous stem cell transplant. This in‐depth reconstitution analysis builds upon what we and others have seen using lower resolution methods in MS and other autoimmune diseases.…”

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

“…64 This mechanism appears to be nondisease-specific and has been reported in other autoimmune diseases. 14,30,31,[36][37][38][65][66][67] Indeed, as already shown in multiple sclerosis, 37 our group of responder SSc patients experienced significantly increased expression of regulatory molecules after AHSCT, when compared with nonresponders. Of note, nonresponder SSc patients presented lower FoxP3 expression before transplantation and consequently lower Treg percentage when compared with responders, indicating a possible selection bias or perhaps a potential biomarker to predict response to AHSCT.…”

“…[36][37][38] Antihuman monoclonal antibodies (mAbs) included the following: CD3 (UCHT1), CD4 (RPA-T4), CD8 (RPA-T8), CD19 (HIB19), CD31 (WM59), CD45RA (HI100), CD45RO (UCHL1), CD27 (L128), CD25 (2A3), immunoglobulin D (IgD) (IA6-2), CD38 (HIT2), CD24 (ML5), and CTLA-4 (BNI3) from BD Pharmingen (San Diego, CA), and GITR (eBioAITR) and FoxP3 (PCH101) from eBioscience (San Diego, CA). Cells were acquired in FACSCalibur (BD Biosciences) cytometer and analyzed with Flow Jo (TreeStar) software.…”