Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Katrine Kielsen , Dina Leth Møller , Anders Elm Pedersen , Claus Henrik Nielsen , Marianne Ifversen , Lars Peter Ryder , Klaus Müller
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引用次数: 0

Abstract

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied.

We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18–3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023).

These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

Abstract Image

巨细胞病毒感染与小儿造血干细胞移植后胸腺功能障碍和慢性移植物抗宿主疾病有关。
小儿造血干细胞移植(HSCT)面临着慢性移植物抗宿主疾病(cGvHD)的挑战,严重影响了存活率和长期发病率,但包括HSCT后CMV感染影响在内的潜在机制却鲜有研究。我们首先调查了2000年至2018年期间接受标准髓鞘脱落造血干细胞移植的322名儿童中CMV感染对cGvHD发生的影响。在一项多变量 Cox 回归分析中,临床上明显的 CMV 感染(n = 61)是慢性 GvHD 的独立风险因素(HR = 2.17,95% CI = 1.18-3.97,P = 0.013)。接下来,我们在 39 名儿童的子队列中探讨了其潜在机制。CMV感染后,近期胸腺移出者(17.5 vs. 51.9 × 106/L,P = 0.048)以及HSCT后6个月的幼稚CD4+和CD8+ T细胞浓度降低(所有P高),包括表达幼稚标记物CD45RA和Helios的Tregs,在CMV感染患者中往往较低(2.9 vs. 9.6 × 106/L,P = 0.055)。CD8+ T细胞数量在CMV感染后上升,并以表达PD1的衰竭细胞为主(66% vs. 39%,P = 0.023)。这些研究结果表明,造血干细胞移植后CMV感染是小儿造血干细胞移植后发生慢性GvHD的主要风险因素,并提示这种影响是由于胸腺功能降低、幼稚T细胞和调节性T细胞的生成持续受损以及外周T细胞衰竭增加造成的。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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