Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation
Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation
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DOI：
10.1182/blood-2005-05-1775
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发表时间：
2005-12-15
期刊：
影响因子：
20.3
通讯作者：
Velardi, A
中科院分区：
文献类型：
--
作者：
Perruccio, K;Tosti, A;Velardi, A
曲霉菌和巨细胞病毒是单倍体相合造血移植后发病率/死亡率的主要原因。这种高度的不匹配使细胞免疫治疗变得不可能，因为它会导致致命的移植物抗宿主病(GvHD)。我们产生了大量针对曲霉菌或巨细胞病毒抗原的供体T细胞克隆。我们通过筛查克隆与受体单个核细胞的交叉反应，确定了可能导致移植物抗宿主病的克隆。移植后不久，非受者反应性、病原体特异性克隆被输注。它们是CD4(+)，产生高水平的干扰素-伽马和低水平的白介素10。在46例未接受过继治疗的对照移植受者中，自发性病原体特异性T细胞在移植后9~12个月出现频率较低，表现为无保护性的低干扰素-γ/高白介素10产生表型。在接受过继治疗的35名受者中，一次输注10(5)至10(6)个/kg体重的供体同种抗原缺失的病原体特异性克隆不会引起GvHD，并诱导对病原体的高频T细胞反应，在输注后3周内表现出保护性的高干扰素-γ/低白介素10的表型。病原体特异性T细胞的频率随着时间的推移保持稳定，并与曲霉、巨细胞病毒抗原血症和感染性死亡的控制有关。这项研究为降低单倍体相合移植后的感染死亡率开辟了新的视角。
Aspergillus and cytomegalovirus are major causes of morbidity/mortality after haploidentical hematopoietic transplantation. The high degree of mismatching makes cell immunotherapy impossible as it would result in lethal graft-versus-host disease (GvHD). We generated large numbers of donor T-cell clones specific for Aspergillus or cytomegalovirus antigens. We identified clones potentially responsible for causing GvHD by screening them for cross-reactivity against recipient mononuclear cells. Nonrecipient reactive, pathogen-specific clones were infused soon after transplantation. They were CD4(+) and produced high levels of interferon-gamma and low levels of interleukin-10. In 46 control transplant recipients who did not receive adoptive therapy, spontaneous pathogen-specific T cells occurred in low frequency 9 to 12 months after transplantation and displayed a non-protective low interferon-gamma/high interleukin-10 production phenotype. In the 35 recipients who received adoptive therapy, one single infusion of donor alloantigen-deleted, pathogen-specific clones in the dose range of 10(5) to 10(6) cells/kg body weight did not cause GvHD and induced high-frequency T-cell responses to pathogens, which exhibited a protective high interferon-gamma/low interleukin-10 production phenotype within 3 weeks of infusion. Frequencies of pathogen-specific T cells remained stable over time, and were associated with control of Aspergillus, and cytomegalovirus antigenemia and infectious mortality. This study opens new perspectives for reducing infectious mortality after haploidentical transplantations.