PDF(Pubmed)
Abstract：
Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.
摘要：
脓毒症,异质性临床综合征,对组织损伤或感染的全身性炎症反应，随后是免疫反应性降低的状态。可测量的改变发生在先天和适应性免疫系统中。免疫麻痹,免疫抑制状态，伴随着恶化的结果，包括多器官功能障碍综合征,继发感染,和死亡率增加。已经提出了多种识别脓毒症免疫麻痹的免疫标记，有些可能提供临床效用。脓毒症免疫麻痹的特征是淋巴细胞数量减少和先天免疫单核细胞上II类人白细胞抗原（HLA）的下调。II类HLA蛋白呈递肽抗原以供抗原特异性T淋巴细胞识别和激活。一种单核细胞II类蛋白，mHLA-DR,可以通过流式细胞术测量。mHLA-DR下调表明单核细胞反应性降低，如通过响应于内毒素刺激的离体细胞因子产生所测量的。我们的文献调查显示，外周血单核细胞的mHLA-DR低表达与感染和死亡风险增加相关。对于mHLA-DR，作为免疫能力的下限,15,000个抗体/细胞在临床上似乎是可接受的。小于15,000个抗体/细胞的值与脓毒症严重程度相关;并且等于或小于8000个抗体/细胞的值被鉴定为严重的免疫麻痹。已经评估了几种实验性免疫疗法对脓毒症免疫麻痹的逆转。特别是,sargramostim,重组人粒细胞-巨噬细胞集落刺激因子（rhuGM-CSF），通过减少住院时间和降低继发感染风险证明了临床益处。这些患者的感染风险降低与外周血单核细胞mHLA-DR表达增加相关。尽管mHLA-DR在鉴定脓毒症免疫麻痹方面显示出很有希望的应用,缺乏标准化，到目前为止，经过分析验证的方法阻止了广泛采用。用于患者纳入和鉴定临床相关输出参数的临床有用的方法可以解决对败血症中的有效靶向治疗的持续高度未满足的医学需求。
