Arruda L C M, Lorenzi J C C, Sousa A P A, Zanette D L, Palma P V B, Panepucci R A, Brum D S, Barreira A A, Covas D T, Simões B P, Silva W A, Oliveira M C, Malmegrim K C R
1] Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil [2] Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Bone Marrow Transplant. 2015 Mar;50(3):380-9. doi: 10.1038/bmt.2014.277. Epub 2014 Dec 8.
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.
自体造血干细胞移植（AHSCT）过去已被作为多发性硬化症（MS）的一种治疗选择进行研究。尽管临床管理取得了进展，但关于移植后临床缓解所涉及机制的认识仍然有限。MS中存在异常的微小RNA和基因表达模式，这些已被认为是疾病生物标志物和潜在的治疗靶点。在此，我们评估了AHSCT后的T细胞和B细胞重建、微小RNA以及免疫调节基因表达。早期免疫重建主要由外周稳态增殖驱动。AHSCT增加了CD4(+)CD25(hi)FoxP3(+)调节性T细胞计数以及CD4(+)CD25(hi) T细胞上CTLA-4和糖皮质激素诱导的TNFR（GITR）的表达。我们发现耗竭的PD-1(+) T细胞和抑制性CD8(+)CD28(-)CD57(+) T细胞短暂增加。在基线时，MS患者的CD4(+)和CD8(+) T细胞呈现出miR-16、miR-155和miR-142-3p上调，而FOXP3、FOXO1、PDCD1和IRF2BP2下调。移植后，FOXP3、FOXO1、PDCD1和IRF2BP2的表达增加，在2年时达到对照水平。miR-16、miR-155和miR-142-3p的表达在治疗后6个月降至正常水平，并在随访结束前一直保持下调。这些数据有力地表明，AHSCT使微小RNA和基因表达正常化，从而改善免疫调节网络。这些机制可能对AHSCT后早期的疾病控制很重要。
