郭軼先(綜述),夏長(zhǎng)青(審校)

(首都醫(yī)科大學(xué)宣武醫(yī)院血液科,北京100053)

抗原特異性免疫耐受治療自身免疫疾病的新進(jìn)展

郭軼先(綜述),夏長(zhǎng)青※(審校)

(首都醫(yī)科大學(xué)宣武醫(yī)院血液科,北京100053)

免疫系統(tǒng)的一個(gè)重要功能是能區(qū)分自身抗原與外源抗原或者是“有害抗原”與“無(wú)害抗原”。自身免疫耐受是指機(jī)體內(nèi)的T、B淋巴細(xì)胞不能對(duì)自身抗原產(chǎn)生免疫應(yīng)答，這一過(guò)程基于一個(gè)復(fù)雜的免疫調(diào)節(jié)網(wǎng)絡(luò)，包括中樞免疫耐受和外周免疫耐受?？乖禺愋悦庖吣褪苤委熓侵冈谧陨砻庖咝约膊∵x擇性的誘導(dǎo)機(jī)體自身免疫耐受，同時(shí)保留對(duì)病毒、真菌和腫瘤抗原的免疫應(yīng)答[1]?，F(xiàn)對(duì)抗原特異性免疫耐受治療自身免得疫疾病的主要方法以及近期在臨床試驗(yàn)中的進(jìn)展進(jìn)行綜述。

1抗原特異性免疫耐受治療的主要方法

1.1針對(duì)自身抗原的免疫耐受誘導(dǎo)方法

1.1.1黏膜免疫耐受黏膜免疫耐受是指經(jīng)口服或經(jīng)鼻吸入途徑攝入某種外源抗原以誘導(dǎo)機(jī)體T 和B淋巴細(xì)胞對(duì)此種外源抗原產(chǎn)生免疫耐受，而對(duì)其他外源抗原仍能維持正常免疫應(yīng)答的誘導(dǎo)方法[2]，黏膜免疫耐受的優(yōu)點(diǎn)包括抗原特異性、幾乎沒(méi)有毒性、便于操作和不良反應(yīng)少。黏膜免疫耐受在動(dòng)物模型中可成功地誘導(dǎo)抗原特異性免疫耐受[2]，然而，目前為止，黏膜免疫耐受在一些自身免疫性疾病的臨床試驗(yàn)中未能顯示出類似于動(dòng)物模型的療效[3-7]。

1.1.2可溶性肽免疫耐受可溶性肽免疫耐受是指重復(fù)多次注射較大劑量的可溶性肽可誘導(dǎo)肽特異性T細(xì)胞無(wú)能或死亡，表現(xiàn)為機(jī)體再次接觸抗原肽后抗原肽特異性T細(xì)胞不能增殖和分泌白細(xì)胞介素2，機(jī)體對(duì)該可溶性肽產(chǎn)生免疫耐受[8-9]?？扇苄噪恼T導(dǎo)抗原特異性免疫耐受的另一個(gè)機(jī)制是可誘導(dǎo)調(diào)節(jié)T細(xì)胞產(chǎn)生，特別是運(yùn)用低劑量可溶性肽進(jìn)行免疫[10]。由于可溶性肽本身具有免疫原性，注射可溶性肽有加重疾病或誘發(fā)過(guò)敏反應(yīng)的風(fēng)險(xiǎn)[11-12]。此外，在自身免疫性疾病發(fā)生過(guò)程中存在表位擴(kuò)展現(xiàn)象。所以在臨床上，單獨(dú)應(yīng)用一種可溶性的肽來(lái)誘導(dǎo)免疫耐受效果并不是很理想[13-15]。為了解決這個(gè)問(wèn)題，有研究者使用混合了多個(gè)可溶性肽的方式來(lái)誘導(dǎo)耐受[16]。

1.1.3變異性肽配體變異性肽配體也稱修飾性肽配體是一種變異抗原，與自然肽配體相比，在與主要組織相容性復(fù)合體(major histocompatibility complex,MHC),或T細(xì)胞受體(T cell receptor,TCR)結(jié)合位置有一個(gè)或數(shù)個(gè)氨基酸被其他氨基酸替換[17]。變異性肽配體作為拮抗劑或半激動(dòng)劑與自身抗原天然肽配體競(jìng)爭(zhēng)性結(jié)合抗原呈遞細(xì)胞(antigen presenting cell,APC)上的MHC或TCR，使T細(xì)胞不能完全激活，繼而引起T細(xì)胞分化信號(hào)改變，T細(xì)胞由輔助性T細(xì)胞(helper T cell，Th)1/Th17向Th2/Th3方向轉(zhuǎn)化[18-19]或者誘導(dǎo)調(diào)節(jié)T細(xì)胞生成來(lái)發(fā)揮特異性免疫調(diào)節(jié)作用[20]。理論上，變異性肽配體本身不具有免疫原性，與直接應(yīng)用表位肽誘導(dǎo)免疫耐受相比更為安全。但是在兩個(gè)多發(fā)性硬化癥(multiple sclerosis，MS)臨床試驗(yàn)中，其中1個(gè)試驗(yàn)包括142例MS患者，由于9%的患者產(chǎn)生了超敏反應(yīng)而暫停了[21]；另1個(gè)試驗(yàn)包括25例患者也中斷了，因?yàn)樵?例患者中觀察到疾病的惡化[22]。

1.2針對(duì)自身反應(yīng)性淋巴細(xì)胞的免疫耐受誘導(dǎo)方法

1.2.1T細(xì)胞疫苗(T cell vaccine,TCV)TCV是指用滅活后的自身反應(yīng)性T細(xì)胞作為疫苗對(duì)自身免疫性疾病進(jìn)行防治[23]。TCV的概念在一定程度上類似于傳染病疫苗接種，只不過(guò)TCV要清除的是自身反應(yīng)性T細(xì)胞。TCV靶抗原包括全減毒T細(xì)胞(通常是通過(guò)照射制備)、TCR或TCR的一部分或者是編碼TCR的DNA。TCV使用安全，耐受性好。更為突出的是，TCV在部分患者中可獲得滿意的治療效果。但是，仍有一些環(huán)節(jié)需要深入研究[24]。目前，針對(duì)多個(gè)不同自身抗原制備不同的T細(xì)胞克隆還存在一定難度。另外TCV免疫的途徑、使用劑量、免疫的次數(shù)、T細(xì)胞的活化、滅活、免疫原性增強(qiáng)等與免疫效應(yīng)有關(guān)的指標(biāo)有待全面考查。

1.2.2DNA疫苗DNA疫苗又稱核酸疫苗或基因疫苗，是編碼免疫原或與免疫原相關(guān)的真核表達(dá)質(zhì)粒DNA(有時(shí)也可是RNA)[25]。DNA疫苗經(jīng)一定途徑進(jìn)入動(dòng)物體內(nèi)，被宿主細(xì)胞攝取后轉(zhuǎn)錄和翻譯表達(dá)出抗原蛋白，此抗原蛋白能刺激機(jī)體產(chǎn)生非特異性和特異性兩種免疫應(yīng)答反應(yīng)，從而起到免疫保護(hù)作用。DNA疫苗在很多方面優(yōu)于傳統(tǒng)疫苗[26]。DNA疫苗在體內(nèi)表達(dá)抗原的更接近于正常的真核結(jié)構(gòu)，抗原可與MHC Ⅰ類和Ⅱ類分子一并呈遞并可引起更廣泛的免疫應(yīng)答，誘導(dǎo)T細(xì)胞反應(yīng)向Th1或Th2方向分化。DNA疫苗可在體內(nèi)持續(xù)表達(dá)免疫原從而能誘導(dǎo)長(zhǎng)期免疫應(yīng)答。相對(duì)于合成肽段，DNA疫苗的優(yōu)點(diǎn)是制備方法穩(wěn)定和造價(jià)低，并且儲(chǔ)存和運(yùn)輸方便。但是，目前DNA疫苗尚缺乏規(guī)范的監(jiān)管，并且理論上還存在一些安全風(fēng)險(xiǎn)，包括插入突變的危險(xiǎn)、原癌基因激活或抑癌基因失活、誘導(dǎo)抗體產(chǎn)生抗DNA抗體等。

1.3以抗原呈遞細(xì)胞為基礎(chǔ)的免疫耐受誘導(dǎo)方法

1.3.1致耐受樹(shù)突狀細(xì)胞(dendritic cell，DC)疫苗致耐受DC或半成熟DC是指可高表達(dá)MHC-Ⅰ類和MHC-Ⅱ類分子和共刺激分子但是不能分泌炎性因子的DC。致耐受DC可有效地誘導(dǎo)調(diào)節(jié)T細(xì)胞產(chǎn)生而不能誘導(dǎo)Th1/Th17反應(yīng)。雖然未成熟DC和致耐受DC均可誘導(dǎo)調(diào)節(jié)T細(xì)胞產(chǎn)生，但是致耐受DC誘導(dǎo)調(diào)節(jié)T細(xì)胞產(chǎn)生有更多的優(yōu)勢(shì)。例如，在炎癥環(huán)境下，致耐受DC比未成熟DC穩(wěn)定[27]。致耐受DC還可通過(guò)使自身反應(yīng)T細(xì)胞失活或凋亡、誘導(dǎo)T細(xì)胞向Th2方向發(fā)展來(lái)誘導(dǎo)免疫耐受[28]。使用體外誘導(dǎo)的致耐受DC偶聯(lián)自身抗原治療自身免疫性疾病，使機(jī)體復(fù)對(duì)該自身抗原的免疫耐受已經(jīng)成為一個(gè)有效的治療手段，并在許多動(dòng)物模型上得到證實(shí)[29]。但是致耐受DC應(yīng)用到臨床上還存在一系列的問(wèn)題，包括DC的來(lái)源和誘導(dǎo)方案、抗原的選擇、最佳的治療方案等。

1.3.2抗原肽偶聯(lián)到1-乙基-3-(3-二甲基氨基丙基)碳酰二亞胺1-乙基-3-(3-二甲基氨基丙基)碳酰二亞胺(1ethyl3(3dimethyllaminopropyl)carbodiie，EDCI)固定的細(xì)胞EDCI是一種水溶性碳二亞胺，可用于抗原肽和細(xì)胞的偶聯(lián)[30]。在缺乏共刺激信號(hào)的條件下，經(jīng)過(guò)ECDI固定的抗原肽偶聯(lián)凋亡細(xì)胞被機(jī)體未成熟/致耐受APC細(xì)胞處理后呈遞給抗原肽特異性T細(xì)胞，誘導(dǎo)抗原肽特異性T細(xì)胞對(duì)該抗原免疫耐受。免疫耐受的誘導(dǎo)和維持可能與調(diào)節(jié)性T細(xì)胞表達(dá)叉頭框蛋白3或分泌抗炎性細(xì)胞因子如白細(xì)胞介素10/轉(zhuǎn)化生長(zhǎng)因子β增多相關(guān)[31]。與可溶性肽相比，這種方法可降低過(guò)敏的風(fēng)險(xiǎn)[12]。在最近的研究中，7種髓鞘抗原肽與患者外周白細(xì)胞偶聯(lián)后應(yīng)用于MS的治療取得了令人鼓舞的結(jié)果[32]。然而，收集和制備足夠數(shù)目的細(xì)胞是廣泛利用此技術(shù)的一個(gè)障礙。另外這一治療價(jià)格昂貴，且必須在嚴(yán)密監(jiān)控條件下由熟練的操作人員進(jìn)行，要求嚴(yán)格的質(zhì)量控制，所以限制了該方法不能在更多的醫(yī)療機(jī)構(gòu)廣泛開(kāi)展。

2抗原特異性免疫耐受治療與自身免疫性疾病

2.1MSMS是以中樞神經(jīng)系統(tǒng)白質(zhì)脫髓鞘病變?yōu)樘攸c(diǎn)的自身免疫性疾病，它是中樞神經(jīng)系統(tǒng)脫髓鞘疾病中最常見(jiàn)、最主要的疾病?；颊咭郧?、中年多見(jiàn)，其臨床特征為發(fā)作性視神經(jīng)、脊髓和腦部的局灶性障礙。因病變累及的部位和髓鞘脫失灶的范圍不同而臨床表現(xiàn)多樣。MS根據(jù)病程主要分為4種亞型：復(fù)發(fā)緩解型，繼發(fā)進(jìn)展型，原發(fā)進(jìn)展型和進(jìn)展復(fù)發(fā)型[33]。表1主要介紹了最近開(kāi)展的MS抗原特異性免疫耐受治療的臨床研究。

表1　各種抗原特異性免疫耐受方法在MS的臨床研究

MS：多發(fā)性硬化癥；TCV：T細(xì)胞疫苗；TCR： T細(xì)胞受體；DC：樹(shù)突狀細(xì)胞

2.21型糖尿病1型糖尿病是糖尿病的一種類型，它與2型糖尿病的發(fā)病機(jī)制完全不同，屬于自體免疫性疾病[44]。1型糖尿病是由于遺傳和環(huán)境等外界因素共同作用于遺傳易感性的個(gè)體，激活T淋巴細(xì)胞介導(dǎo)的自身抗原耐受破壞而導(dǎo)致的一種器官特異性的自身免疫性疾病，從而引起選擇性胰島細(xì)胞破壞和功能衰竭，體內(nèi)胰島素分泌不足進(jìn)行性加重而導(dǎo)致糖尿病。患者必須注射胰島素治療。表2主要介紹了最近開(kāi)展的1型糖尿病抗原特異性免疫耐受治療的臨床研究。

表2　各抗原特異性免疫耐受方法在1型糖尿病的臨床研究

DC：樹(shù)突狀細(xì)胞

2.3類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis，RA)RA是一種由自身免疫障礙引致免疫系統(tǒng)攻擊關(guān)節(jié)的致殘性關(guān)節(jié)病變。病理特征主要表現(xiàn)為滑膜細(xì)胞異常增殖和炎性細(xì)胞浸潤(rùn)，累及周身關(guān)節(jié)滑膜炎及血管翳形成，嚴(yán)重時(shí)可侵蝕軟骨與骨導(dǎo)致關(guān)節(jié)破壞，造成關(guān)節(jié)變形直至殘廢，并會(huì)因關(guān)節(jié)痛楚及磨損而失去部分活動(dòng)能力。這種病癥亦會(huì)引起關(guān)節(jié)外的病變，包括皮膚、血管、心臟、肺部及肌肉等。本病具體的病理機(jī)制至今未明，尚缺乏有效的治療策略[47]。表3主要介紹了最近開(kāi)展的RA抗原特異性免疫耐受治療的臨床研究。

表3　各抗原特異性免疫耐受方法在RA的臨床研究

RA：類風(fēng)濕關(guān)節(jié)炎；TCV：T細(xì)胞疫苗；TCR：T細(xì)胞受體

3結(jié)語(yǔ)

以抗原為基礎(chǔ)的免疫耐受誘導(dǎo)治療在多種自身免疫性疾病動(dòng)物模型中成功應(yīng)用，但是應(yīng)用到臨床試驗(yàn)中還存在一定的困難，目前的研究趨勢(shì)是使用多種變異自身抗原混合進(jìn)行免疫耐受治療。以自身反應(yīng)性T細(xì)胞為基礎(chǔ)的免疫耐受治療在自身免疫病的臨床試驗(yàn)中取得了令人鼓舞的研究結(jié)果，但是如何確定并獲得自身反應(yīng)性T細(xì)胞是這一治療的關(guān)鍵。DC在維持免疫耐受和免疫應(yīng)答平衡的重要作用已得到共識(shí)，以致耐受DC為基礎(chǔ)的免疫耐受誘導(dǎo)治療已在動(dòng)物實(shí)驗(yàn)中取得了很好的效果，并且開(kāi)展了Ⅰ期臨床試驗(yàn)?？乖悸?lián)細(xì)胞的免疫耐受誘導(dǎo)治療同樣在動(dòng)物模型中取得了很好的效果，但是轉(zhuǎn)化到臨床上還存在很多技術(shù)挑戰(zhàn)，尚不能大規(guī)模開(kāi)展。

參考文獻(xiàn)

[1]Li L,Boussiotis VA.Physiologic regulation of central and peripheral T cell tolerance:lessons for therapeutic applications[J].J Mol Med (Berl),2006,84(11):887-899.

[2]Ilan Y.Oral tolerance:can we make it work? [J].Hum Immunol,2009,70(10):768-776.

[3]Fourlanos S,Perry C,Gellert SA,etal.Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes[J].Diabetes,2011,60(4):1237-1245.

[4]Landewe RB,Houbiers JG,Van den Bosch F,etal.Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis:a phase II,multicentre,double-blind,randomised,placebo-controlled,parallel-group,dose-finding trial[J].Ann Rheum Dis,2010,69(9):1655-1659.

[5]Zandbelt MM,Houbiers JG,van den Hoogen FH,etal.Intranasal administration of recombinant human cartilage glycoprotein-39.A phase I escalating cohort study in patients with rheumatoid arth-ritis[J].J Rheumatol,2006,33(9):1726-1733.

[6]Harrison LC,Honeyman MC,Steele CE,etal.Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes[J].Diabetes Care,2004,27(10):2348-2355.

[7]Hauselmann HJ,Caravatti M,Seifert B,etal.Can collagen type II sustain a methotrexate-induced therapeutic effect in patients with long-standing rheumatoid arthritis? A double-blind,randomized trial[J].Br J Rheumatol,1998,37(10):1110-1117.

[8]Zonneveld-Huijssoon E,Albani S,Prakken BJ,etal.Heat shock protein bystander antigens for peptide immunotherapy in autoimmune disease[J].Clin Exp Immunol,2013,171(1):20-29.

[9]Racke MK,Critchfield JM,Quigley L,etal.Intravenous antigen administration as a therapy for autoimmune demyelinating disease[J].Ann Neurol,1996,39(1):46-56.

[10]Massey EJ,Sundstedt A,Day MJ,etal.Intranasal peptide-induced peripheral tolerance:the role of IL-10 in regulatory T cell function within the context of experimental autoimmune encephalomyelitis[J].Vet Immunol Immunopathol,2002,87(3/4):357-372.

[11]Genain CP,Abel K,Belmar N,etal.Late complications of immune deviation therapy in a nonhuman primate[J].Science,1996,274(5295):2054-2057.

[12]Smith CE,Eagar TN,Strominger JL,etal.Differential induction of IgE-mediated anaphylaxis after soluble vs.cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis[J].Proc Natl Acad Sci U S A,2005,102(27):9595-9600.

[13]Koffeman EC,Genovese M,Amox D,etal.Epitope-specific immunotherapy of rheumatoid arthritis:clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind,placebo-controlled,pilot phase Ⅱ trial[J].Arthritis Rheum,2009,60(11):3207-3216.

[14]Huurman VA,van der Meide PE,Duinkerken G,etal.Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type Ⅰ diabetes[J].Clin Exp Immunol，2008,152(3):488-497.

[15]Goodkin DE,Shulman M,Winkelhake J,etal.A phase Ⅰ trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis[J].Neurology,2000,54(7):1414-1420.

[16]Dolgin E.The inverse of immunity[J].Nat Med,2010,16(7):740-743.

[17]Bielekova B,Martin R.Antigen-specific immunomodulation via altered peptide ligands[J].J Mol Med (Berl),2001,79(10):552-565.

[18]Singh RA,Zhang JZ.Differential activation of ERK,p38,and JNK required for Th1 and Th2 deviation in myelin-reactive T cells induced by altered peptide ligand[J].J Immunol,2004,173(12):7299-7307.

[19]Uhlin M,Masucci M,Levitsky V.Is the activity of partially agonistic MHC:peptide ligands dependent on the quality of immunological help?[J].Scand J Immunol,2006,64(6):581-587.

[20]Fischer FR,Santambrogio L,Luo Y,etal.Modulation of experimental autoimmune encephalomyelitis:effect of altered peptide ligand on chemokine and chemokine receptor expression[J].J Neuroimmunol,2000,110(1/2):195-208.

[21]Kappos L,Comi G,Panitch H,etal.Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled,randomized phase II trial.The Altered Peptide Ligand in Relapsing MS Study Group[J].Nat Med,2000,6(10):1176-1182.

[22]Bielekova B,Goodwin B,Richert N,etal.Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis:results of a phase II clinical trial with an altered peptide ligand[J].Nat Med,2000,6(10):1167-1175.

[23]Ben-Nun A,Wekerle H,Cohen IR.Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein[J].Nature,1981,292(5818):60-61.

[24]Hellings N,Raus J,Stinissen P.T-cell vaccination in multiple sclerosis:update on clinical application and mode of action[J].Autoimmun Rev,2004,3(4):267-275.

[25]Fissolo N,Montalban X,Comabella M.DNA-based vaccines for multiple sclerosis:current status and future directions[J].Clin Immunol,2012,142(1):76-83.

[26]Saha R,Killian S,Donofrio RS.DNA vaccines:a mini review[J].Recent Pat DNA Gene Seq,2011,5(2):92-96.

[27]Lutz MB.Therapeutic potential of semi-mature dendritic cells for tolerance induction[J].Front Immunol,2012,3:123.

[28]Gross CC,Jonuleit H,Wiendl H.Fulfilling the dream:tolerogenic dendritic cells to treat multiple sclerosis[J].Eur J Immunol,2012,42(3):569-572.

[29]Van Brussel I,Lee WP,Rombouts M,etal.Tolerogenic dendritic cell vaccines to treat autoimmune diseases:can the unattainable dream turn into reality?[J].Autoimmun Rev,2014,13(2):138-150.

[30]Miller SD,Wetzig RP,Claman HN.The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells[J].J Exp Med,1979,149(3):758-773.

[31]Smith CE,Miller SD.Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities[J].J Autoimmun,2006,27(4):218-231.

[32]Lutterotti A,Yousef S,Sputtek A,etal.Antigen-specific tolerance by autologous myelin peptide-coupled cells:a phase 1 trial in multiple sclerosis[J].Sci Transl Med,2013,5(8):175-188r.

[33]Nakahara J,Maeda M,Aiso S,etal.Current concepts in multiple sclerosis:autoimmunity versus oligodendrogliopathy[J].Clin Rev Allergy Immunol,2012,42(1):26-34.

[34]Hafler DA,Kent SC,Pietrusewicz MJ,etal.Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis[J].Ann N Y Acad Sci,1997,19(835):120-131.

[35]Warren KG,Catz I,Wucherpfennig KW.Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis[J].J Neurol Sci,1997,152(1):31-38.

[36]Khan O,Rieckmann P,Boyko A,etal.Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis[J].Ann Neurol,2013,73(6):705-713.

[37]Jokubaitis VG,Spelman T,Lechner-Scott J,etal.The Australian Multiple Sclerosis (MS) immunotherapy study:a prospective,multicentre study of drug utilisation using the MSBase platform[J].PLoS One,2013,8(3):e59694.

[38]Arnold DL,Narayanan S,Antel S.Neuroprotection with glatiramer acetate:evidence from the PreCISe trial[J].J Neurol,2013,260(7):1901-1906.

[39]Karussis D,Shor H,Yachnin J,etal.T cell vaccination benefits relapsing progressive multiple sclerosis patients:a randomized,double-blind clinical trial[J].PLoS One,2012,7(12):e50478.

[40]Fox E,Wynn D,Cohan S,etal.A randomized clinical trial of autologous T-cell therapy in multiple sclerosis:subset analysis and implications for trial design[J].Mult Scler,2012,18(6):843-852.

[41]Vandenbark AA,Culbertson NE,Bartholomew RM,etal.Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis[J].Immunology,2008,123(1):66-78.

[42]Garren H,Robinson WH,Krasulova E,etal.Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis[J].Ann Neurol,2008,63(5):611-620.

[43]Raiotach-Regue D,Grau-Lopez L,Naranjo-Gomez M,etal.Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients[J].Eur J Immunol,2012,42(3):771-782.

[44]Eisenbarth GS.Type I diabetes mellitus.A chronic autoimmune disease[J].N Engl J Med,1986,314(21):1360-1368.

[45]Walter M,Philotheou A,Bonnici F,etal.No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes[J].Diabetes Care,2009,32(11):2036-2040.

[46]Giannoukakis N,Phillips B,Finegold D,etal.Phase Ⅰ (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients[J].Diabetes Care,2011,34(9):2026-2032.

[47]Macfarlane GJ,El-Metwally A,De Silva V,etal.Evidence for the efficacy of complementary and alternative medicines in the management of rheumatoid arthritis:a systematic review[J].Rheumatology(Oxford),2011,50(9):1672-1683.

[48]Ivanova IP,Seledtsov VI,Seledtsov DV,etal.Characterization of immunogenic properties of polyclonal T cell vaccine intended for the treatment of rheumatoid arthritis[J].Bull Exp Biol Med,2007,144(4):630-634.

[49]Moreland LW,Morgan EE,Adamson TR,etal.T cell receptor peptide vaccination in rheumatoid arthritis:a placebo-controlled trial using a combination of Vbeta3,Vbeta14,and Vbeta17 peptides[J].Arthritis Rheum,1998,41(11):1919-1929.

摘要：自身免疫性疾病是機(jī)體對(duì)自身抗原的免疫耐受機(jī)制破壞，導(dǎo)致一個(gè)或多個(gè)器官的免疫性損傷。目前，大多數(shù)自身免疫性疾病的治療策略仍是長(zhǎng)期使用免疫抑制藥物，其主要問(wèn)題是缺乏免疫抑制的特異性，長(zhǎng)期使用可抑制正常免疫效應(yīng)細(xì)胞的功能，導(dǎo)致嚴(yán)重的甚至危及患者生命的不良反應(yīng)，因此，臨床上需要特異性的、低毒性和更加長(zhǎng)效的治療手段以治療自身免疫性疾病。

關(guān)鍵詞：自身免疫性疾病;免疫耐受;抗原特異;樹(shù)突狀細(xì)胞

Progress in the Treatment of Antigen Specific Immune Tolerance for Autoimmune DiseasesGUOYi-xian,XIAChang-qing.(DepartmentofHematology,CapitalMedicalUniversityXuanwuHospital,Beijing100053,China)

Abstract:Autoimmune diseases can cause immune damages of one or more organs as a result of breaking the balance of body′s immune tolerance to auto-antigen.At present,the strategy of most autoimmune diseases treatment is still based on long-term use of immunosuppressive drugs which lack of antigen-specificity and inhibit the normal function of the immune effector cells and cause severe and sometimes life-threatening side effects.Therefore,antigen-specific lower toxic and longer effective treatments are needed for autoimmune diseases in clinical.

Key words:Autoimmune diseases; Immune tolerance; Antigen specific; Dendritic cells

收稿日期：2014-09-29修回日期：2015-01-12編輯：相丹峰

doi：10.3969/j.issn.1006-2084.2015.16.010

中圖分類號(hào):R593.2

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)16-2906-04