Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients

Abstract

Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T-and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4 + CD25 hi FoxP3 + regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4 + CD25 hi T cells. We found transient increase in exhausted PD-1 + T cells and of suppressive CD8 + CD28 − CD57 + T cells. At baseline, CD4 + and CD8 + T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.

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.…”

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

“…Suppression of inflammatory activity after AHSCT was associated with regeneration of the T-cell compartment [26]. Increased numbers of regulatory T-cells (Treg) after A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 transplantation indicate reestablishment of immune balance [27][28][29]. In addition, depletion of IL-17-producing mucosal-associated invariant T-cells [27] and diminished Th17 responses [28] have been described.…”

Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis

“…After 1-2 years, there is an expansion of naïve CD4 and CD8 T cells that have a thymic origin with a broader clonal diversity and clonal specificity. There is also an increase of regulatory CD4+, CD24 high , CD127 -, Fox3 + T cells 22 . Similar changes occur in the B repertoire.…”