Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Department of Neurology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Front Immunol. 2022 Feb 7;13:798300. doi: 10.3389/fimmu.2022.798300. eCollection 2022.
Autologous haematopoietic stem cell transplantation (AHSCT) is a vital therapeutic option for patients with highly active multiple sclerosis (MS). Rates of remission suggest AHSCT is the most effective form of immunotherapy in controlling the disease. Despite an evolving understanding of the biology of immune reconstitution following AHSCT, the mechanism by which AHSCT enables sustained disease remission beyond the period of lymphopenia remains to be elucidated. Auto-reactive T cells are considered central to MS pathogenesis. Here, we analyse T cell reconstitution for 36 months following AHSCT in a cohort of highly active MS patients. Through longitudinal analysis of sorted naïve and memory T cell clones, we establish that AHSCT induces profound changes in the dominant T cell landscape of both CD4+ and CD8+ memory T cell clones. Lymphopenia induced homeostatic proliferation is followed by clonal attrition; with only 19% of dominant CD4 (p <0.025) and 13% of dominant CD8 (p <0.005) clones from the pre-transplant repertoire detected at 36 months. Recovery of a thymically-derived CD4 naïve T cell repertoire occurs at 12 months and is ongoing at 36 months, however diversity of the naïve populations is not increased from baseline suggesting the principal mechanism of durable remission from MS after AHSCT relates to depletion of putative auto-reactive clones. In a cohort of MS patients expressing the MS risk allele HLA DRB1*15:01, public clones are probed as potential biomarkers of disease. AHSCT appears to induce sustained periods of disease remission with dynamic changes in the clonal T cell repertoire out to 36 months post-transplant.
自体造血干细胞移植 (AHSCT) 是治疗高度活跃型多发性硬化症 (MS) 患者的重要治疗选择。缓解率表明，AHSCT 是控制疾病最有效的免疫疗法形式。尽管人们对 AHSCT 后免疫重建的生物学有了不断的认识，但 AHSCT 如何在淋巴细胞减少期之外实现持续缓解疾病的机制仍有待阐明。自身反应性 T 细胞被认为是 MS 发病机制的核心。在这里，我们分析了一组高度活跃的 MS 患者在 AHSCT 后 36 个月的 T 细胞重建情况。通过对分选的幼稚和记忆 T 细胞克隆进行纵向分析，我们确定 AHSCT 诱导了 CD4+和 CD8+记忆 T 细胞克隆的主要 T 细胞景观发生深刻变化。淋巴细胞减少诱导的稳态增殖后是克隆耗竭；只有 19%的移植前 CD4（p<0.025）和 13%的移植前 CD8（p<0.005）克隆在 36 个月时被检测到。胸腺来源的 CD4 幼稚 T 细胞库在 12 个月时恢复，并且在 36 个月时仍在继续，但幼稚群体的多样性没有从基线增加，这表明 AHSCT 后 MS 持久缓解的主要机制与潜在自身反应性克隆的耗竭有关。在一组表达 MS 风险等位基因 HLA DRB1*15:01 的 MS 患者中，探测公共克隆作为疾病的潜在生物标志物。AHSCT 似乎在移植后 36 个月内诱导持续的疾病缓解期，并伴有克隆 T 细胞库的动态变化。
