沙利度胺对甲型H1N1流感患者细胞因子和细胞免疫功能的影响
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摘要
研究目的：本研究旨在观察细胞因子和T细胞亚群在甲型H1N1流感患者中的变化趋势,评价沙利度胺对甲型H1N1流感患者细胞因子和T淋巴细胞亚群的影响。
研究方法：观察2009年12月至2010年2月入住昆明医学院第一附属医院ICU科的20例确诊甲型H1N1流感患者。以沙利度胺给药前氧合指数200为界限进行分组,分为氧合指数>200组和氧合指数<200组,监测两组细胞因子和T淋巴细胞亚群的变化趋势。
研究结果：1.白介素-2(IL-2)：与氧合指数>200组相比,入院及治疗第一天氧合指数<200组的IL-2明显增高,P<0.05。2.白介素-4(IL-4)：与氧合指数>200组相比,治疗第三天氧合指数<200组IL-4明显增高,P<0.05。3.白介素-6(IL-6)：总体均数明显呈下降趋势,由27.26±27.88 pg／ml下降至1.15±0.51 pg/ml。与氧合指数>200组相比,入院及治疗第一天氧合指数<200组IL-6明显增高,P<0.05。4.白介素-10(IL-10)：与氧合指数>200组相比,入院及治疗第三天氧合指数<200组IL-10明显增高,P<0.05。5.肿瘤坏死因子-α(TNF-α)：总体均数明显呈下降趋势,由37.56±48.48 pg／ml下降至6.25±9.29 pg／ml。与氧合指数>200组相比,氧合指数<200组TNF-α明显增高,且P<0.05。6.总T淋巴细胞：总T淋巴细胞的总体均数明显升高,与氧合指数>200组相比,入院时氧合指数<200组总T淋巴细胞明显降低,且P<0.05。7.T辅助淋巴细胞(Th细胞)：治疗第三天、第五天与入院时相比,呈明显升高趋势,P<0.05。8.T抑制淋巴细胞(Ts细胞)：治疗第一天、第三天、第五天与入院时相比,呈明显升高趋势,均有统计学意义,P<0.05。9.NK淋巴细胞：氧合指数>200组相比,氧合指数<200组NK淋巴细胞明显降低,治疗后第一天,第三天,第五天均有统计学意义,且P<0.05。10.Th／Ts：氧合指数<200组,治疗第五天的Th／Ts比值比第三天明显升高,P<0.05。
研究结论：1.甲型H1N1流感危重症患者(氧合指数<200)的细胞因子IL-2、IL-6、IL-10和TNF--比氧合指数>200组的高。2.甲型H1N1流感患者总T淋巴细胞和T辅助淋巴细胞水平均降低,细胞免疫功能下降；甲型H1N1流感危重症患者的总T淋巴细胞、T辅助淋巴细胞、T抑制淋巴细胞、Th／Ts比值和NK淋巴细胞比氧合指数>200组的低。3.使用沙利度胺治疗后,致炎性因子IL-2、IL-6和TNF-a水平较前明显下降,而总T淋巴细胞、T辅助淋巴细胞和T抑制淋巴细胞水平较前明显升高。
Aim:This study aimed to investigate the tendency of cytokines and T lymphocyte subsets in cases of pandemic H1N1 2009 and evaluate the effect of thalidomide on cytokines and T lymphocyte subsets of influenza A/H1N1 patients.
Method:During 12,2009 and 2,2010, we observed 20 patients infected influenza A (H1N1) virus who were admited in Intensive Care Unit of the First Affiliated Hospital of Kunming Medical College. Oxygenation index of 200 as the boundary point before thalidomide was given, they were divided into the oxygenation index> 200 group and oxygenation index< 200 group, and the change of cytokines and T lymphocyte subsets were monitored.
Result:1.Interleukin-2 (IL-2):Compared with oxygenation index>200, IL-2 significantly increased on the day of admission and the first day of treatment in oxygenation index<200, and P<0.05.2. Interleukin-4 (IL-4):Compared with oxygenation index>200, IL-4 markedly increased on the third day of therapy in oxygenation index<200, and P<0.05.3. Interleukin-6 (IL-6):The mean of IL-6 significantly decreased from 27.26±27.88 pg/ml to 1.15±0.51 pg/ml. Compared with oxygenation index>200, IL-6 obviously on the day of admission and the first day of therapy in oxygenation index<200, and P＜0.05.4. Interleukin-10 (IL-10):Compared with oxygenation index>200, IL-10 obviously increased on the day of admission and the third of therapy in oxygenation index<200 group, and P<0.05.5. Tumor necrosis factor-a (TNF-a):The mean of TNF-a significantly decreased from 37.56±48.48 pg/ml to 6.25±9.29 pg/ml. Compared with oxygenation index>200, TNF-a significantly increased in oxygenation index<200, and P<0.05.6. Total T lymphocyte:The mean of total T lymphocyte obviously increased with therapy and total T cell significantly decreased on the day of admission in oxygenation index<200 group compared with oxygenation index>200, and P<0.05.7. T-helper lymphocyte (Th):T-helper lymphocyte amount increased with therapy. There was significantly higher on the third and the fifth day than the day of admission, and P<0.05.8. T-supressor lymphocyte (Ts):,T-supressor lymphocyte amount increased with therapy. There was significantly higher on the first, the third, the fifth day than the day of admission, and P<0.05.9. NK lymphocyte (NK):Compared with oxygenation index >200, NK amount significantly decreased on the first, the third and the fifth day of therapy, and P<0.05.10. Th/Ts:Th/Ts ratio was significantly higher on the fifth day than on the third day of therapy, P<0.05.
Conclusions:1.IL-2, IL-6, IL-10 and TNF-a were higher in severe cases of pandemic H1N12009 influenza virus infection (oxygenation index<200) than oxygenation index>200 group.2. Total T cells amount and T-helper lymphocyte amount decreased in cases of H1N1 2009 influenza virus infection, and cellular immune function of patients was damaged; Total T cells amount, T-helper lymphocyte amount, T-supressor lymphocyte amount, NK lymphocyte amount and Th/Ts ratio decreased in severe cases than oxygenation index>200 group.3. After thalidomide was given, proinflammatory factors (IL-2, IL-6, TNF-a) decreased, but the amount of total T cells, Th and Ts increased.
研究方法：观察2009年12月至2010年2月入住昆明医学院第一附属医院ICU科的20例确诊甲型H1N1流感患者。以沙利度胺给药前氧合指数200为界限进行分组,分为氧合指数>200组和氧合指数<200组,监测两组细胞因子和T淋巴细胞亚群的变化趋势。
研究结果：1.白介素-2(IL-2)：与氧合指数>200组相比,入院及治疗第一天氧合指数<200组的IL-2明显增高,P<0.05。2.白介素-4(IL-4)：与氧合指数>200组相比,治疗第三天氧合指数<200组IL-4明显增高,P<0.05。3.白介素-6(IL-6)：总体均数明显呈下降趋势,由27.26±27.88 pg／ml下降至1.15±0.51 pg/ml。与氧合指数>200组相比,入院及治疗第一天氧合指数<200组IL-6明显增高,P<0.05。4.白介素-10(IL-10)：与氧合指数>200组相比,入院及治疗第三天氧合指数<200组IL-10明显增高,P<0.05。5.肿瘤坏死因子-α(TNF-α)：总体均数明显呈下降趋势,由37.56±48.48 pg／ml下降至6.25±9.29 pg／ml。与氧合指数>200组相比,氧合指数<200组TNF-α明显增高,且P<0.05。6.总T淋巴细胞：总T淋巴细胞的总体均数明显升高,与氧合指数>200组相比,入院时氧合指数<200组总T淋巴细胞明显降低,且P<0.05。7.T辅助淋巴细胞(Th细胞)：治疗第三天、第五天与入院时相比,呈明显升高趋势,P<0.05。8.T抑制淋巴细胞(Ts细胞)：治疗第一天、第三天、第五天与入院时相比,呈明显升高趋势,均有统计学意义,P<0.05。9.NK淋巴细胞：氧合指数>200组相比,氧合指数<200组NK淋巴细胞明显降低,治疗后第一天,第三天,第五天均有统计学意义,且P<0.05。10.Th／Ts：氧合指数<200组,治疗第五天的Th／Ts比值比第三天明显升高,P<0.05。
研究结论：1.甲型H1N1流感危重症患者(氧合指数<200)的细胞因子IL-2、IL-6、IL-10和TNF--比氧合指数>200组的高。2.甲型H1N1流感患者总T淋巴细胞和T辅助淋巴细胞水平均降低,细胞免疫功能下降；甲型H1N1流感危重症患者的总T淋巴细胞、T辅助淋巴细胞、T抑制淋巴细胞、Th／Ts比值和NK淋巴细胞比氧合指数>200组的低。3.使用沙利度胺治疗后,致炎性因子IL-2、IL-6和TNF-a水平较前明显下降,而总T淋巴细胞、T辅助淋巴细胞和T抑制淋巴细胞水平较前明显升高。
Aim:This study aimed to investigate the tendency of cytokines and T lymphocyte subsets in cases of pandemic H1N1 2009 and evaluate the effect of thalidomide on cytokines and T lymphocyte subsets of influenza A/H1N1 patients.
Method:During 12,2009 and 2,2010, we observed 20 patients infected influenza A (H1N1) virus who were admited in Intensive Care Unit of the First Affiliated Hospital of Kunming Medical College. Oxygenation index of 200 as the boundary point before thalidomide was given, they were divided into the oxygenation index> 200 group and oxygenation index< 200 group, and the change of cytokines and T lymphocyte subsets were monitored.
Result:1.Interleukin-2 (IL-2):Compared with oxygenation index>200, IL-2 significantly increased on the day of admission and the first day of treatment in oxygenation index<200, and P<0.05.2. Interleukin-4 (IL-4):Compared with oxygenation index>200, IL-4 markedly increased on the third day of therapy in oxygenation index<200, and P<0.05.3. Interleukin-6 (IL-6):The mean of IL-6 significantly decreased from 27.26±27.88 pg/ml to 1.15±0.51 pg/ml. Compared with oxygenation index>200, IL-6 obviously on the day of admission and the first day of therapy in oxygenation index<200, and P＜0.05.4. Interleukin-10 (IL-10):Compared with oxygenation index>200, IL-10 obviously increased on the day of admission and the third of therapy in oxygenation index<200 group, and P<0.05.5. Tumor necrosis factor-a (TNF-a):The mean of TNF-a significantly decreased from 37.56±48.48 pg/ml to 6.25±9.29 pg/ml. Compared with oxygenation index>200, TNF-a significantly increased in oxygenation index<200, and P<0.05.6. Total T lymphocyte:The mean of total T lymphocyte obviously increased with therapy and total T cell significantly decreased on the day of admission in oxygenation index<200 group compared with oxygenation index>200, and P<0.05.7. T-helper lymphocyte (Th):T-helper lymphocyte amount increased with therapy. There was significantly higher on the third and the fifth day than the day of admission, and P<0.05.8. T-supressor lymphocyte (Ts):,T-supressor lymphocyte amount increased with therapy. There was significantly higher on the first, the third, the fifth day than the day of admission, and P<0.05.9. NK lymphocyte (NK):Compared with oxygenation index >200, NK amount significantly decreased on the first, the third and the fifth day of therapy, and P<0.05.10. Th/Ts:Th/Ts ratio was significantly higher on the fifth day than on the third day of therapy, P<0.05.
Conclusions:1.IL-2, IL-6, IL-10 and TNF-a were higher in severe cases of pandemic H1N12009 influenza virus infection (oxygenation index<200) than oxygenation index>200 group.2. Total T cells amount and T-helper lymphocyte amount decreased in cases of H1N1 2009 influenza virus infection, and cellular immune function of patients was damaged; Total T cells amount, T-helper lymphocyte amount, T-supressor lymphocyte amount, NK lymphocyte amount and Th/Ts ratio decreased in severe cases than oxygenation index>200 group.3. After thalidomide was given, proinflammatory factors (IL-2, IL-6, TNF-a) decreased, but the amount of total T cells, Th and Ts increased.
引文
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[2]Kelsey FO. Thalidomide update:regulatory aspects. Teratology.1988; 38:221-226.
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[4]Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl Med.1999; 341:1565-1571.
[5]Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide:identification of prognostic factors in a phage study of 169 patients. Blood.2001; 98:492-494.
[6]Moreira ALL, Tsenova-Berkova J, Wang P, et al. Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis. Tuberc Lung Dis.1997; 78: 47-55.
[7]Gori AF, Franzetti G, Marchetti C, et al. Clinical and immunological improvement in a patient who received thalidomide treatment for refractory M. avium complex infection. Clin Infect Dis.1998; 26:184-185.
[8]Milazzo L, Biasin, Hekill G, et al.Thallidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin. American Journal of Gastroenterology.2006; 101:399-402.
[9]Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest, 2002; 122:227-232.
[10]Karim MY, Ruiz-Irastorza G, Khamashta MA, et al. Update on therapy:thalidomide in the treatment of lupus. Lupus.2001; 10:188-192.
[11]Julkunen I,Melen K,Nyqvist M,et al. Infummatory responses in influenza A virus infection. Vaccine 2000;19(suppl 1):S32-S37.
[12]Julkunen I,SarenevaT.Prirhonen J,et al. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev 2001;12:171-180.
[13]Sprenger H,Meyer RG,KaufmannA,et al. Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. J Exp Med 1996;184:1191-1196.
[14]Adachi M,Matsukura S,Toukunaga H,et al. Expression of cytokines on human bronchial epithelial cells induced by influenza virus A. Int Arch Allergy Immunol 1997;113:307-311.
[15]Chan MC,Cheung CY,Chui WH,et al. Proinflammatory cytokine responses induced by influenza A(H5N1) viruses in primary human alveolar and brochial epithelial cells. Respir Res 2005;6:135.
[16]Ada GL,Jones PD. The immune response to influenza infection. Curr Top Microbiol Immunol 1986;128:1-54.
[17]Schmitz N, Kurrer M, Bachmann MF, et al. Interlerkin-1 is responsible for acute lung immunopathologhy but increases survival of respiratory influenza virus infection. J Virol. 2005; 79:6441-6448.
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[21]Peper RL,Van Campen H. Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia. Microb Pathog 1995;19:175-183.
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1996;184:1191-1196.
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[28]Spittler A,Razenberger M,Kupper H,et al. Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production [J].Clin Infect Dis,2000,31 (6):1338～1420.
[29]Q.Ye,B.Chen,Z.Tong,et al.Thalidomide reduces IL-18, IL-8 and TNF-a release from alveolar macrophages in interstitial lung disease[J]. European Respiratory Journal 2006;28:824-831
[30]金惠铭,王建枝；病理生理学(第七版)；北京人民出版社101-103
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