張 典 高興春 姜鳳良 彌 曼

(西安醫(yī)學(xué)院醫(yī)學(xué)免疫學(xué)教研室，陜西 西安 710021)

?

·綜 述·

多糖的免疫調(diào)節(jié)作用研究進(jìn)展

張 典 高興春 姜鳳良 彌 曼1

(西安醫(yī)學(xué)院醫(yī)學(xué)免疫學(xué)教研室，陜西 西安 710021)

多糖；免疫調(diào)節(jié)；腫瘤

隨著增齡老年人免疫功能逐漸降低。免疫相關(guān)疾病，如慢性炎癥、腫瘤等疾病發(fā)病率不斷提高。真菌多糖具有免疫調(diào)節(jié)、抗炎和抗腫瘤等活性。多糖作為天然活性物質(zhì)，最大的優(yōu)點(diǎn)是毒副作用極小，來源廣泛。本文通過PubMed搜索關(guān)于多糖的文章(只包括以英文發(fā)表的文章)，目的是通過評(píng)估關(guān)于多糖的特異性免疫效果，為多糖化合物免疫調(diào)節(jié)作用研究提供理論依據(jù)。

1 多糖對(duì)健康人群和動(dòng)物免疫功能的影響

在健康動(dòng)物研究中的結(jié)果表明：各種葡聚糖產(chǎn)品的免疫刺激作用，包括赭鱗蘑菇(赭鱗蘑菇多糖水提取物)〔1〕、香菇(香菇多糖)〔2〕、釀酒酵母(β-1,3-葡聚糖)〔3,4〕、海帶(昆布多糖)〔5〕、桑黃(桑黃多糖水，乙醇沉淀提取)〔6〕、西洋參、三島柴胡(呋喃糖)等〔7,8〕，可以增強(qiáng)健康動(dòng)物的免疫功能。瓜爾豆半乳甘露聚糖(瓜爾膠)或高甲氧基果膠誘導(dǎo)老年動(dòng)物抗體的分泌〔9〕。對(duì)于健康的成年人，食用裙帶菜中褐藻糖膠提取物，發(fā)現(xiàn)既有免疫刺激又有免疫抑制的作用，包括增加CD34+細(xì)胞數(shù)量；刺激基質(zhì)細(xì)胞衍生因子-1(stromal-derived factor-1)、干擾素(IFN)-γ分泌；降低血液中白細(xì)胞和淋巴細(xì)胞數(shù)量〔10〕。從西洋參中提取的三七呋喃糖可明顯降低健康老年人急性呼吸道疾病的發(fā)病率和癥狀持續(xù)時(shí)間〔11〕。

2 多糖抗感染、抗炎和抗過敏作用

口服多糖抗感染、抗炎和抗過敏作用已得到證實(shí)。口服燕麥中水溶性葡聚糖的動(dòng)物與給予巰基乙酸鹽、氯膦酸鹽或單純皰疹病毒I型(HSV-I)注射,具有明顯的抗感染和抗炎作用〔12,13〕?？诜ゲ级嗵堑膭?dòng)物感染大腸桿菌和口服啤酒酵母多糖的動(dòng)物感染金黃色葡萄球菌、白色的動(dòng)物念珠菌后，均表現(xiàn)出多糖的抗感染作用〔14,15〕。釀酒酵母β-1,3、1-6葡聚糖降低成人季節(jié)性過敏性鼻炎患者IL-4、IL-5水平和嗜酸性粒細(xì)胞百分比，同時(shí)增加鼻分泌液中IL-12的含量〔16〕。炎癥性腸病動(dòng)物模型表明，巖藻聚糖硫酸酯〔17〕、瓜爾豆半乳甘露聚糖〔18〕、蘋果果膠〔19〕、混合多糖補(bǔ)充劑〔20〕，均有明顯的抗炎作用。多糖通過增強(qiáng)機(jī)體的非特異性免疫功能，如提高血清溶菌酶活性、增強(qiáng)NK細(xì)胞的細(xì)胞毒作用等，抵抗病原微生物的侵襲。本課題組使用致炎劑(葡聚糖硫酸鈉)和致癌劑(氧化偶氮甲烷)，建立小鼠結(jié)腸炎相關(guān)結(jié)直腸癌動(dòng)物模型，發(fā)現(xiàn)蘋果渣中提取的蘋果多糖可顯著預(yù)防小鼠結(jié)腸炎相關(guān)結(jié)直腸癌的發(fā)生，其機(jī)制與抑制TLR4/NF-κB通路有關(guān)〔21〕。

3 多糖抗癌作用

自從20世紀(jì)50年代發(fā)現(xiàn)真菌多糖具有抗癌作用后，又發(fā)現(xiàn)地衣、花粉等許多植物均含有多糖類化合物，并進(jìn)行分離提純，確定了其化學(xué)結(jié)構(gòu)、物理化學(xué)性質(zhì)、藥理作用，尤其對(duì)多糖類化合物的抗腫瘤作用進(jìn)行深入研究。大量的腫瘤動(dòng)物模型均顯示多糖具有抗腫瘤作用。來自蘑菇的水提取物或水、酸處理后得到的葡聚糖均有抗癌作用〔22〕。研究發(fā)現(xiàn)靈芝多糖提取物〔23〕、海帶多糖〔24〕、香菇多糖〔25〕、釀酒酵母多糖〔26〕、蘋果多糖〔21〕，均可降低腫瘤的發(fā)生率。癌細(xì)胞植入動(dòng)物體內(nèi)，建立動(dòng)物腫瘤模型后，給予云芝多糖，發(fā)現(xiàn)云芝多糖可降低腫瘤生長速度和血管密度〔27〕。寧夏枸杞多糖、香菇多糖和蘑菇多糖被證明可活化腫瘤動(dòng)物模型的免疫系統(tǒng)〔28〕。

臨床研究顯示云芝多糖可以通過增加血液中NK細(xì)胞活性，淋巴細(xì)胞的細(xì)胞毒作用，輔助性T細(xì)胞的比例，提高晚期胃癌、結(jié)腸癌和直腸癌患者的生存率〔23〕。Tsang等〔29〕研究顯示，晚期肺癌病人使用云芝多糖，可增加抗體IgM 、IgG和白細(xì)胞總數(shù)和中性粒細(xì)胞計(jì)數(shù)。Ahn等〔30〕進(jìn)行的卵巢或子宮內(nèi)膜癌患者隨機(jī)對(duì)照試驗(yàn)顯示，蘑菇葡聚糖可增加NK細(xì)胞活性和減少化療的副作用。蘆薈多糖的人體試驗(yàn)結(jié)果顯示可增加維生素C和E血漿的生物利用度〔31〕。多糖的攝入對(duì)營養(yǎng)素和藥物吸收的影響，目前還不清楚。

在嚙齒類動(dòng)物急性和慢性毒性試驗(yàn)顯示，多糖產(chǎn)品是安全的〔32～34〕。目前多糖產(chǎn)品因?yàn)檫€沒有得到充分的結(jié)構(gòu)特征證明，這一點(diǎn)已成為關(guān)注熱點(diǎn)。

4 多糖對(duì)免疫功能的作用〔35〕

考慮到消化道極其復(fù)雜的環(huán)境，研究者據(jù)此推測，部分水解的腸道細(xì)菌多糖片段可以結(jié)合到腸上皮細(xì)胞，發(fā)揮對(duì)局部或全身免疫系統(tǒng)的影響；或被吸收入血，可能對(duì)各組織器官產(chǎn)生的影響。研究表明〔35〕植物多糖能明顯提高環(huán)磷酰胺所致免疫抑制小鼠腹腔巨噬細(xì)胞的吞噬百分?jǐn)?shù)及吞噬指數(shù)；顯著刺激小鼠B淋巴細(xì)胞增殖，提高小鼠巨噬細(xì)胞RAW264.7吞噬中性紅的能力以及RAW264.7分泌NO的能力；增強(qiáng)NK細(xì)胞的細(xì)胞毒作用并促進(jìn)IL-2的產(chǎn)生；顯著提高CD4/CD8陽性細(xì)胞百分率；促進(jìn)脾細(xì)胞中細(xì)胞因子IL-2的mRNA表達(dá)。另外，多糖能夠減少免疫抑制劑諸如細(xì)胞毒性、機(jī)體抗感染能力下降、對(duì)骨髓造血細(xì)胞的生長抑制等副作用〔27〕。目前，學(xué)者們利用代謝組學(xué)和基因組學(xué)，檢測和跟蹤多糖，正在研究多糖的生物轉(zhuǎn)化，包括它們的生物利用度和其代謝過程。多糖類膳食調(diào)節(jié)劑，需要更好探討多糖攝入的最佳時(shí)機(jī)和持續(xù)時(shí)間。只有少數(shù)報(bào)道，已經(jīng)研究了多糖的攝取時(shí)間以實(shí)現(xiàn)最佳效益。目前明確，蘑菇多糖其免疫效果依賴于合用益生元〔27〕。

文獻(xiàn)中記錄的多種膳食多糖，包括口服攝入的葡聚糖、果膠、雜聚糖、葡甘露聚糖、巖藻聚糖硫酸酯、半乳甘露聚糖、阿拉伯半乳聚糖和混合多糖產(chǎn)品對(duì)于嚙齒類動(dòng)物有明顯影響。對(duì)不同動(dòng)物組織具有免疫調(diào)節(jié)作用，包括血液、胃腸道和脾。另外，多糖的攝入，對(duì)健康成人降低呼吸道致炎劑過敏反應(yīng)、提高腫瘤患者的生存率都有一定作用。葡聚糖、阿拉伯半乳聚糖、巖藻聚糖硫酸酯對(duì)健康成人和口腔潰瘍患者具有一定的免疫調(diào)節(jié)作用。但多糖文獻(xiàn)是高度異源的，并沒有提供多糖產(chǎn)品結(jié)構(gòu)等。安全性和毒性研究表明，這些多糖產(chǎn)品在很大程度上有很好的耐受性。這次文獻(xiàn)綜述對(duì)多糖的免疫調(diào)節(jié)、指導(dǎo)未來的研究提供了理論基礎(chǔ)。

1 Chan Y,Chang T,Chan CH,etal.Immunomodulatory effects of Agaricus blazei murill in Balb/cByJ mice〔J〕.J Microbiol Immunol Infect,2007;40(3):201-8.

2 Harada K,Itashiki Y,Takenawa T,etal.Effects of lentinan alone and in combination with fluoropyrimidine anticancer agent on growth of human oral squamous cell carcinoma in vitro and in vivo〔J〕.Int J Oncol,2010;37(3):623-31.

3 Vetvicka V,Vashishta A,Saraswat-Ohri S,etal.Immunological effects of yeast-and mushroom-derived beta-glucans〔J〕.J Med Food,2008;11(4):615-22.

4 Tsukada C,Yokoyama H,Miyaji C,etal.Immunopotentiation of intraepithelial lymphocytes in the intestine by oral administrations of beta-glucan〔J〕.Cell Immunol,2003;221(1):1-5.

5 Sweeney T,Collins CB,Reilly P,etal.Effect of purified β-glucans derived from Laminaria digitata,Laminaria hyperborea and Saccharomyces cerevisiae on piglet performance,selected bacterial populations,volatile fatty acids and pro-inflammatory cytokines in the gastrointestinal tract of pigs 〔J〕.Br J Nutr,2012;108(7):1226-34.

6 Oh GS,Lee MS,Pae HO,etal.Effects of oral administration of phellinus linteus on the production of Th1-and Th2-type cytokines in mice 〔J〕.Immunopharmacol Immunotoxicol,2006;28(2):281-93.

7 Biondo PD,Goruk S,Ruth MR,etal.Effect of CVT-E002(COLD-fX)versus a ginsenoside extract on systemic and gut-associated immune function 〔J〕.Int Immunopharmacol,2008;8(8):1134-42.

8 Sakurai MH,Matsumoto T,Kiyohara H,etal.B-cell proliferation activity of pectic polysaccharide from a medicinal herb,the roots of Bupleurum falcatum L.and its structural requirement 〔J〕.Immunology,1999;97(3):540-7.

9 Yamada K,Tokunaga Y,Ikeda A,etal.Effect of dietary fiber on the lipid metabolism and immune function of aged Sprague-Dawley rats 〔J〕.Biosci Biotechnol Biochem,2003;67(2):429-33.

10 Irhimeh MR,Fitton JH,Lowenthal RM,etal.Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells〔J〕.Exp Hematol,2007;35(6):989-94.

11 McElhaney JE,Goel V,Toane B,etal.Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults:a randomized,double-blinded,placebo controlled trial 〔J〕.J Altern Complement Med,2006;12(2):153-7.

12 Murphy EA,Davis JM,Carmichael MD,etal.Benefits of oat beta-glucan and sucrose feedings on infection and macrophage antiviral resistance following exercise stress 〔J〕.Am J Physiol Regul Integr Comp Physiol,2009;297(4):1188-94.

13 Murphy EA,Davis JM,Brown AS,etal.Oat beta-glucan effects on neutrophil respiratory burst activity following exercise 〔J〕.Med Sci Sports Exerc,2007;39(4):639-44.

14 Neyrinck AM,Mouson A,Delzenne NM,etal.Dietary supplementation with laminarin,a fermentable marine beta(1-3)glucan,protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue 〔J〕.Int Immunopharmacol,2007;7(12):1497-506.

15 Rice PJ,Adams EL,Ozment-Skelton T,etal.Oral delivery and gastrointestinal absorption of soluble glucans stimulate increased resistance to infectious challenge 〔J〕.J Pharmacol Exp Ther,2005;314(3):1079-86.

16 Kirmaz C,Bayrak P,Yilmaz O,etal.Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis:a double-blind placebo-controlled study 〔J〕.Eur Cytokine Netw,2005;16(2):128-34.

17 Nakazato K,Takada H,Iha M,etal.Attenuation of N-nitrosodiethylamine-induced liver fibrosis by high-molecular-weight fucoidan derived from Cladosiphon okamuranus 〔J〕.J Gastroenterol Hepatol,2010;25(10):1692-701.

18 Naito Y,Takagi T,Katada K,etal.Partially guar gum down-regulates colonic inflammatory response in dextran sulfate sodium-induced colitis in mice 〔J〕.J Nutr Biochem,2006;17(6):402-9.

19 Moriarty PM,Backes J,Dutton JA,etal.Apple pectin for the reduction of niacin-induced flushing 〔J〕.J Clin Lipidol,2013;7(2):140-6.

20 Koetzner L,Grover G,Boulet J,etal.Plant-derived polysaccharide dietary supplements inhibits dextran sulfate sodium-induced colitis in the rat 〔J〕.Dig Dis Sci,2010;55(5):1278-85.

21 Zhang D,Mi M,Jiang F,etal.Apple polysaccharide reduces NF-kB mediated colitis-associated colon carcinogenesis 〔J〕.Nutr Cancer,2015;67(1):177-90.

22 Murakawa K,Fukunaga K,Tanouchi M,etal.Therapy of myeloma in vivo using marine phospholipid in combination with Agaricus blazei Murill as an immune respond activator 〔J〕.J Oleo Sci,2007;56(4):179-88.

23 Li A,Shuai X,Jia Z,etal.Ganoderma lucidum polysaccharide extract inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation and function by inducing microRNA-125b 〔J〕.J Transl Med,2015;26(13):100.

24 Zhai Q,Li X,Yang Y,etal.Antitumor activity of a polysaccharide fraction from Laminaria japonica on U14 cervical carcinoma-bearing mice 〔J〕.Tumour Biol,2014;35(1):117-22.

25 Sun M,Zhao W,Xie Q,etal.Lentinan reduces tumor progression by enhancing gemcitabine chemotherapy in urothelial bladder cancer 〔J〕.Surg Oncol,2015;24(1):28-34.

26 Aleem E.β-Glucans and their applications in cancer therapy:focus on human studies 〔J〕.Anticancer Agents Med Chem,2013；13(5):709-19.

27 Piotrowski J,Jedrzejewski T,Kozak W,etal.Immunomodulatory and antitumor properties of polysaccharide peptide(PSP)〔J〕.Postepy Hig Med Dosw(Online),2015；21:91-7.

28 Jeurink PV,van Esch BC,Rijnierse A,etal.Mechanisms underlying immune effects of dietary oligosaccharides 〔J〕.Am J Clin Nutr,2013;98(2):572S-577S.

29 Tsang KW,Lam CL,Yan C,etal.Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer 〔J〕.Respir Med,2003;97(6):618-24.

30 Ahn WS,Kim DJ,Chae GT,etal.Natural killer cell activity and quality of life were improved by consumption of a mushroom extract,Agaricus blazei Murill Kyowa,in gynecological cancer patients undergoing chemotherapy 〔J〕.Int J Gynecol Cancer,2004;14(4):589-94.

31 Vinson JA,Al Kharrat H,Andreoli L,etal.Effect of Aloe vera preparations on human bioavailability of vitamins C and E 〔J〕.Phytomedicine,2005;12(10):760-5.

32 Tamboli S,Arora S,Bhatnagar U,etal.Reproductive and developmental toxicity evaluation of a purified Arabinogalactan-Protein(AGP)composition in Wistar rats 〔J〕.Fitoterapia,2010;81(4):276-83.

33 Kim KJ,Lee OH,Lee HH,etal.A 4-week repeated oral dose toxicity study of fucoidan from the Sporophyll of Undaria pinnatifida in Sprague-Dawley rats 〔J〕.Toxicology,2010;267(1-3):154-8.

34 Moura Neto E,Sombra VG,Richter AR,etal.See comment in PubMed commons below chemically sulfated galactomannan from Dimorphandra gardneriana seed:characterization and toxicity evaluation 〔J〕.Carbohydr Polym,2014;30(101):1013-7.

35 Kothari D,Patel S,Goyal A,etal.Therapeutic spectrum of nondigestible oligosaccharides:overview of current state and prospect〔J〕.J Food Sci,2014;79(8):1491-8.

〔2016-01-30修回〕

(編輯 曲 莉)

國家自然科學(xué)基金資助項(xiàng)目(No.81402063)；陜西省教育廳項(xiàng)目(No.15JK1636)；西安醫(yī)學(xué)院校級(jí)課題(No.2015DOC09)

彌 曼(1960-)，女，教授，主要從事腫瘤藥理學(xué)研究。

張 典(1976-)，女，博士，副教授，主要從事腫瘤免疫藥理學(xué)研究。

R284

A

1005-9202(2016)21-5448-03；

10.3969/j.issn.1005-9202.2016.21.107

1 西安醫(yī)學(xué)院藥理學(xué)教研室