Nitsche Andreas, Zhang Meixia, Clauss Theresa, Siegert Wolfgang, Brune Kay, Pahl Andreas
Charité - CCM, CC14 Haematology/Oncology, Charitéplatz 1, 10117 Berlin, Germany.
BMC Immunol. 2007 Aug 31;8:18. doi: 10.1186/1471-2172-8-18.
Stem cell transplantation as therapy for hematological disorders is often hampered by severe graft-versus-host-disease. This may be reduced by umbilical cord blood transplantation, an effect that has been attributed to qualitative differences between neonatal and adult T cells. We compared levels of secreted proteins and cytokine mRNA induced in cord blood leukocytes (CBL) and adult blood leukocytes (ABL) by various stimuli.
While interleukin-2 (IL-2) levels were similar in CBL and ABL, there was less induction of the Th1 cytokine interferon-gamma in CBL. Production of the Th2 cytokines IL-4, IL-5, and IL-13 and the hematopoietic cytokine IL-3 was much lower in CBL versus ABL after T-cell receptor-mediated stimulation, whereas production of GM-CSF was comparable in the 2 cell types. The lower levels of Th1 and Th2 cytokines were maintained in CBL during a 4-day time-course study, while after 12 hours IL-3 and GM-CSF reached in CBL levels similar to those in ABL. For all cytokines except IFN gamma, the IC50 values for inhibition by cyclosporin A were similar in ABL and CBL. In contrast, there was less expression and activation of transcription factors in CBL. Activation of NF-kappaB by TPA/ionomycin was detected in ABL but not CBL. Furthermore, there was less expression of the Th subset-specific transcription factors T-bet and c-maf in CBL versus ABL, whereas GATA-3 expression was similar. Expression of T-bet and c-maf correlated with expression of the Th1 and Th2 cytokines, respectively. Time course experiments revealed that T-bet expression was stimulated in both cell types, whereas c-maf and GATA-3 were induced only in ABL.
The diminished capability of CBL to synthesize cytokines is probably due to decreased activation of NF-kappaB, whereas differences in Th subsets are due to differences in regulation of Th lineage-specific transcriptions factors. We propose that the reduced incidence and severity of GvHD after allogeneic transplantation of umbilical CB cells is due to lesser activation of specific transcription factors and a subsequent reduction in production of certain cytokines.
干细胞移植作为血液系统疾病的治疗方法，常因严重的移植物抗宿主病而受阻。脐带血移植可能会降低这种情况，这种效果归因于新生儿和成人T细胞之间的质量差异。我们比较了各种刺激物诱导脐带血白细胞（CBL）和成人血白细胞（ABL）分泌的蛋白质和细胞因子mRNA的水平。
虽然CBL和ABL中的白细胞介素-2（IL-2）水平相似，但CBL中Th1细胞因子干扰素-γ的诱导较少。在T细胞受体介导的刺激后，CBL中Th2细胞因子IL-4、IL-5和IL-13以及造血细胞因子IL-3的产生远低于ABL，而GM-CSF在两种细胞类型中的产生相当。在为期4天的时间进程研究中，CBL中Th1和Th2细胞因子的水平保持较低，而12小时后CBL中IL-3和GM-CSF达到与ABL相似的水平。除IFNγ外，环孢素A抑制所有细胞因子的IC50值在ABL和CBL中相似。相反，CBL中转录因子的表达和激活较少。在ABL中检测到TPA/离子霉素激活NF-κB，但在CBL中未检测到。此外，与ABL相比，CBL中Th亚群特异性转录因子T-bet和c-maf的表达较少，而GATA-3表达相似。T-bet和c-maf的表达分别与Th1和Th2细胞因子的表达相关。时间进程实验表明，两种细胞类型中T-bet表达均受到刺激，而c-maf和GATA-3仅在ABL中被诱导。
CBL合成细胞因子的能力下降可能是由于NF-κB激活减少，而Th亚群的差异是由于Th谱系特异性转录因子调控的差异。我们提出，同种异体脐带血移植后移植物抗宿主病的发生率和严重程度降低是由于特定转录因子的激活较少以及随后某些细胞因子产生的减少。
