Brodszki Nicholas, Turkiewicz Dominik, Toporski Jacek, Truedsson Lennart, Dykes Josefina
Children's Hospital, Skåne University Hospital, Lund, Sweden.
Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden.
Orphanet J Rare Dis. 2016 Jan 15;11:5. doi: 10.1186/s13023-016-0385-3.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for severe combined immunodeficiency (SCID); although, there is a high incidence of severe infections and an increased risk of graft-versus host-disease (GvHD) with HSCT. Early intervention is a crucial prognostic factor and a HLA-haploidentical parental donor is often available. Haploidentical HSCT protocols utilizing extensively ex vivo T-cell depleted grafts (CliniMACs system) have proven efficient in preventing GvHD, but cause a delay in early T-cell recovery that increases the risk of viral infections. Here, we present a novel approach for treating SCID that combines selective depletion of GvHD-inducing alpha/beta (α/β) T-cells from the haploidentical HSCT graft with a subsequent donor lymphocyte infusion (DLI) enriched for CD45RO+ memory T-cells.
Our patient was diagnosed with SCID (T-B + NK+ phenotype). At 9 months of age, he received a T cell receptor(TCR)α/β-cell depleted graft from his haploidentical mother, following a reduced intensity conditioning regimen with no additional GvHD prophylaxis. Engraftment was rapid with complete donor chimerism and no signs of GvHD. However, at 12 weeks post HSCT, the patient was still T-cell lymphopenic with clinical symptoms of multiple severe viral infections. Consequently, therapeutic DLIs were initiated for enhanced anti-viral immunity. The patient was treated with CD45RA+ depleted haploidentical maternal donor lymphocytes enriched from unmobilized whole blood, and a total T-cell dose of no more than 25 x10(3) CD3+ cells/kg with >99.9% purity of CD3 + CD45RO+ memory T-cells was transferred. Following the DLI, a prompt increase in CD3 + CD4+ and CD3 + CD8+ counts was observed with a subsequent clearance of viral infections. No acute or chronic GvHD was observed.
Automated depletion of CD45RA+ naïve T-cells from unmobilized whole blood is a simple and rapid strategy to provide unmanipulated DLIs, with a potentially broad repertoire of pathogen specific memory T-cells. In the haploidentical setting, CD45RA+ depleted DLIs can be safely administered at low T-cell doses for efficient enhancement of viral immunity and limited risk of GvHD. We demonstrate the successful use of this approach following TCR-α/β-cell depleted HSCT for the treatment of SCID.
异基因造血干细胞移植（HSCT）是治疗重症联合免疫缺陷（SCID）的唯一有效疗法；然而，HSCT存在严重感染的高发生率以及移植物抗宿主病（GvHD）风险增加的问题。早期干预是一个关键的预后因素，且通常可获得HLA单倍型相合的亲代供体。利用体外广泛去除T细胞的移植物（CliniMACs系统）的单倍型相合HSCT方案已被证明在预防GvHD方面有效，但会导致早期T细胞恢复延迟，从而增加病毒感染风险。在此，我们提出一种治疗SCID的新方法，该方法将从单倍型相合HSCT移植物中选择性去除诱导GvHD的α/β T细胞与随后输注富含CD45RO +记忆T细胞的供体淋巴细胞（DLI）相结合。
我们的患者被诊断为SCID（T - B + NK +表型）。9个月大时，在采用降低强度预处理方案且未进行额外GvHD预防的情况下，他接受了来自其单倍型相合母亲的T细胞受体（TCR）α/β细胞去除的移植物。植入迅速，供体完全嵌合，且无GvHD迹象。然而，HSCT后12周，患者仍存在T细胞淋巴细胞减少，并伴有多种严重病毒感染的临床症状。因此，启动了治疗性DLI以增强抗病毒免疫力。患者接受了从未动员的全血中富集的去除CD45RA + 的单倍型相合母亲供体淋巴细胞治疗，转移的总T细胞剂量不超过25×10³ CD3 + 细胞/kg，CD3 + CD45RO + 记忆T细胞纯度>99.9%。DLI后，观察到CD3 + CD4 + 和CD3 + CD8 + 计数迅速增加，随后病毒感染得到清除。未观察到急性或慢性GvHD。
从未动员的全血中自动去除CD45RA + 初始T细胞是一种简单快速的策略，可提供未经过处理的DLI，其具有潜在广泛的病原体特异性记忆T细胞库。在单倍型相合的情况下，去除CD45RA + 的DLI可以低T细胞剂量安全给药，以有效增强病毒免疫力且GvHD风险有限。我们证明了这种方法在TCR - α/β细胞去除的HSCT治疗SCID后成功应用。
