免疫抑制剂在肾移植中的应用进展

www.yongyao.net　　2009-7-22 13:10:15　　来源：　　责任编辑：

分享到：

3　免疫抑制剂应用方面存在的问题及应用方案的改良免疫抑制剂是一把“双刃剑”,无论对移植受者及移植器官的短期及长期存活都具有重要的影响,在过去的几十年时间里,大量免疫抑制剂的应用,在控制早期、晚期排斥反应和感染(如CMV感染)取得了明显进展,但受者和移植物存活率明显提高的同时也不可避免的带来了感染、肿瘤(皮肤癌、淋巴瘤等) 、骨髓抑制、肾毒性和肝毒性(多见于钙调节免疫抑制剂) 、高血压、高血脂及糖尿病等并发症。同时晚期移植肾失功比率仍然很高。调查显示全美国肾移植受者每年约有4500例移植肾失功,已成为导致终末期肾脏疾病( ESRD)的主要原因之一。因此,选择更专一性的药物、避免肾毒性药物联用和对毒性保持高度的警惕就显得尤为重要。近年来对免疫抑制剂应用方案也有了不少新的探索。

3.1　小剂量或撤除激素方案　糖皮质激素是肾移植术后免疫治疗方案的经典组份,但长期使用不良反应十分明显。Nowacka2Cieciura E等^{[ 30 ]}研究表明,小剂量强的松治疗组的血糖和血脂控制、骨密度均优于常规剂量强的松治疗组,并且不良反应减少,受者/移植肾存活率并未受影响,作者认为在受者良好的免疫抑制剂反应性和药物浓度监测下撤除激素对肾移植受者是有利的。Woodle ES等^{[ 31, 32 ]}在肾移植早期使用巴昔单抗( basilix2imab) + FK506 + Rapa的联合用药方案成功地取代了皮质类固醇激素类药物。同时研究发现MMF +FK506 + 早期停用类固醇较MMF + FK506 + 长期低剂量类固醇的用药方案效果显著。但国外一项荟萃分析^{[ 33 ]}显示,激素撤药增加了移植肾失功的相对危险性及发生急性排斥的危险性。尽管越来越多学者倾向于撤出激素方案,但由于激素在治疗急性排斥反应中的特殊地位以及缺乏大样本长期临床研究结果,因此,是否撤除激素尚需综合考虑。

3.2　低剂量或转换CN I方案　CN I包括CSA 和FK506,肾移植受者应用CN I达到预防排斥反应的剂量,将会使这些患者的肾小球滤过率减少15% ～25%。持续应用CN I会导致慢性移植物肾病(CAN)的发展,而CAN则是引起移植肾晚期失功的主要原因,故近年提出以CN I为基础的治疗变为以非CN I为基础的转换治疗。在MMF出现以前,撤退CSA 急排发生率上升11%;在MMF出现以后,撤退CSA,移植肾功能及高血压控制则有明显好转。Kasiske BL等^{[ 33 ]}的文献荟萃分析显示撤除CN I对发生AR的相对危险度无显著差异,在选择的病例中, CSA撤除对长期移植肾衰竭的危险性影响似乎很少。Stallone G等^{[ 34 ]}作了尸体肾移植后3个月撤除CSA的随机对照研究,结果发现术后12月撤除CSA组与有CSA组比较,中重度慢性移植肾肾病发生率明显下降,肌酐清除率明显上升,提示早期撤除CSA在尸体肾移植是安全可行的。临床选用CN I时,应制订个体的免疫抑制方案。在特异性免疫耐受的诱导尚未成功之前,免疫抑制剂仍是肾移植不可替代的治疗手段。

3.3　免疫诱导治疗方案　诱导治疗能够有效降低肾移植早期急性排斥的发生。移植前诱导治疗主要包括多克隆抗淋巴细胞抗体[抗胸腺细胞球蛋白(ATG)和抗淋巴细胞球蛋白(ALG) ]及单抗淋巴细胞抗体(OKT3、抗CD25单抗等)的使用。近年来关于骨髓造血干细胞输注诱导肾移植免疫耐受的报道较多,本中心^{[ 35 ]}研究发现骨髓输注组急性排斥发生率明显低于对照组,分别为3117%与12181% ,并提示输注能促进术后早期嵌合体的形成,显著降低急性排斥发生率及减少远期排斥发生的趋势。最近Scandling JD等^{[ 36 ]}利用造血干细胞输注诱导肾移植免疫耐受,结果经过造血干细胞输注诱导的6例患者中有4例受试者在停止使用免疫抑制剂下安全存活超过28 个月,该鼓舞人心的结果今年已在《新英格兰杂志》发表,成为今后免疫耐受诱导的一个重要方向。所有这些新的诱导治疗方案都将有助于减少激素和CN I的用量,提高移植物长期存活。

4　总结及展望

肾移植开展半个多世纪以来,随着对移植免疫认识的深入,在免疫抑制剂上取得了很大的进步,但是令人满意的免疫抑制剂和免疫抑制方案还需不断探索。对未来免疫抑制剂美好远景是:高效、低毒、高度选择性免疫抑制,这样既能保持移植物长期存活,又能提高患者生活质量。本中心研究发现在中国人群中采用低剂量的环孢素、骁悉、强的松三联免疫抑制治疗可以明显降低肺部感染的发生但不增加急性排斥的发生^{[ 37 ]} 。因而,肾脏移植受者免疫抑制剂应用应该遵循个体化原则,对不同个体“量体裁衣”,应用最适免疫抑制剂组合和剂量,达到不良反应与疗效的最优化。免疫抑制剂个体化应用需要解决的核心问题是建立器官移植受者免疫状态以及免疫抑制剂药代动力、基因多态性及药物毒理动力的监测、识别与评价指标体系,这也是目前及今后免疫抑制剂应用的发展趋势。

【参考文献】
[ 1 ] FirstMR1 An update on new immunosupp ressive drugs undergoing p reclinical and clinical trials: potential app lications in organ transp lantation[ J ]1Am J Kidney Dis, 1997, 29 (2) : 30323171
[ 2 ] Gummert JF, Ikonen T, Morris RE1 Newer immunosupp ressive drugs: areview[ J ]1J Am Soc Nephrol, 1999, 10 (6) : 1366213801
[ 3 ] 何强, 陈江华, 王逸民1 两种包含他克莫司的免疫抑制方案在肾移植中的应用体会[ J ]1中华器官移植杂志, 2002, 23 (5) : 28422851
[ 4 ] CherikhWS, Myron KH,Maghirang J, et al1A comparison of discharge immunosupp ressive drug regimens in p rimary cadaveric kidney transp lantation[ J ]1Transp lantation, 2003, 76 (3) : 46324701
[ 5 ] Dudley C, Pohanka E, Riad H, et al1 Mycophenolate mofetil substitution for cyclosporine a in renal transp lant recip ients with chronic p rogressive allograft dysfunction: the“creep ing creatinine”study[ J ]. Transp lantation, 2005, 79 (4) : 46624751
[ 6 ] KarinM1New twists in gene regulation by glucocorticoid recep tor: isDNAbinding dispensable[ J ]1Cell, 1998, 93 (4) : 48724901
[ 7 ] Jordan SC, Vo A, Bunnap radist S, et al1 Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transp lantation of incompatible organs in living2donor and cadaver recip ients[ J ]1Transp lantation, 2003, 76 (4) : 63126361
[ 8 ] Sehgal SN1Rapamune (RAPA, rapamycin, sirolimus) : mechanism of action immunosupp ressive effect results from blockade of signal transduction and inhibition of cell cycle p rogression [ J ]1 Clin Biochem, 1998, 31(5) : 33523401
[ 9 ] Wilczek HE,Brattstrom C1Sirolimus experience at a Swedish transp lantation center[ J ]1Transp lant Proc, 2003, 35 (3 Supp l) : 84S288S1
[ 10 ]Georgakis GV, YounesA1From Rapa Nui to rapamycin: targeting P I3K/Akt/mTOR for cancer therapy[ J ] 1Expert Rev Anticancer Ther, 2006, 6(1) : 13121401
[ 11 ] Stallone G, Schena A, Infante B, et al1Sirolimus for Kaposips Sarcoma in Renal2Transp lant Recip ients[ J ]1N Engl J Med, 352: 13171
[ 12 ]Brinkmann V, Cyster JG, Hla T1FTY720: sphingosine 12phosphate recep tor21 in the control of lymphocyte egress and endothelial barrier function[ J ]1Am J Transp lant, 2004, 4 (7) : 1019210251
[ 13 ] Budde K, Schmouder RL, Brunkhorst R, et al1First human trial of FTY720, a novel immunomodulator, in stable renal transp lant patients[ J ]1J Am Soc Nephrol, 2002, 13 (4) : 1073210831
[ 14 ]Lamontagne K, Littlewood EA, Schnell C, et al1Antagonism of sphingo sine212phosphate recep tors by FTY720 inhibits angiogenesis and tumor vascularization[ J ]1Cancer Res, 2006, 66 (1) : 22122311
[ 15 ] Strand V, Cohen S, SchiffM, et al1Treatment of active rheumatoid arthri2 tiswith leflunomide compared with p lacebo and methotrexate1 Leflunomide Rheumatoid Arthritis Investigators Group [ J ] 1Arch Intern Med,1999, 159 (21) : 2542225501
[ 16 ]Hardinger KL,Wang CD, SchnitzlerMA, et al1Prospective, p ilot, openlabel, short2term study of conversion to leflunomide reverses chronic renal allograft dysfunction[ J ]1Am J Transp lant, 2002, 2 (9) : 86728711
[ 17 ]Changelian PS, FlanaganME,Ball DJ, et al1Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor [ J ] 1Science, 2003, 302(5646) : 87528781
[ 18 ]Yabu JM,Vincenti F1Novel immunosupp ression: smallmolecules and biologics[ J ]1Semin Nephrol, 2007, 27 (4) : 47924861
[ 19 ] Tamura K,Woo J,BakriMT, et al1Brequinar sodium inhibits interleukin 62induced differentiation of a human B2cell line into IgM2secreting p lasma cells[ J ]1 Immunology, 1993, 79 (4) : 58725931
[ 20 ] Kahan BD1Concentration2controlled immunosupp ressive regimens using cyclosporine with sirolimus or brequinar in human renal transp lantation[ J ]1Transp lant Proc, 1995, 27 (1) : 332361
[ 21 ]Keown PA,Balshaw R, KruegerH, et al1Economic analysis of basiliximab in renal transp lantation[ J ]1Transp lantation, 2001, 71 (11) : 1573215791
[ 22 ]Vincenti F, Kirkman R, Light S, et al1 Interleukin222recep tor blockade with daclizumab to p revent acute rejection in renal transp lantation1 Daclizumab Trip le Therapy Study Group [ J ] 1N Engl J Med, 1998, 338 ( 3) :16121651
[ 23 ]陈忠华,徐逸1CD25单克隆抗体在临床肾移植中的应用[ J ] 1肾脏病与透析肾移植杂志, 2005, 14 (1) : 482491
[ 24 ]Vincenti F,Larsen C,Durrbach A, et al1Costimulation blockade with belatacep t in renal transp lantation[ J ]1N Engl J Med, 2005, 353 ( 8) : 77027811
[ 25 ]Chavez H,Beaudreuil S,Abbed K, et al1Absence of CD4CD25 regulatoryT cell expansion in renal transp lanted patients treated in vivo with Belatacep tmediated CD282CD80 /86 blockade[ J ] 1Transp l Immunol, 2007, 17(4) : 24322481
[ 26 ]Rostaing L, ChabannierMH,Modesto A, et al1Predicting factors of longterm results ofOKT3 therapy for steroid resistant acute rejection followingcadaveric renal transp lantation [ J ] 1Am J Nephrol, 1999, 19 ( 6 ) : 63426401
[ 27 ]Vincenti F, Mendez R, Pescovitz M, et al1A phase Ⅰ /Ⅱ randomized open labelmulticenter trial of efalizumab, a humanized anti2CD11a, an2
ti2LFA21 in renal transp lantation [ J ] 1Am J Transp lant, 2007, 7 ( 7 ) :1770217771
[ 28 ]Knechtle SJ, Pirsch JD, Fechner JJ, et al1Campath21H induction p lus rapamycin monotherapy for renal transp lantation: results of a p ilot study [ J ]1Am J Transp lant, 2003, 3 (6) : 72227301
[ 29 ]Abderrahim E, Karoui C, SmaouiW, et al1Anti2CD20 antibodies to treat lymphop roliferative syndromes following renal transp lantation [ J ]. Transp lant Proc, 2003, 35 (7) : 2708227091
[ 30 ]Nowacka CE, Durlik M, Cieciura T, et al1Steroid withdrawal after renal
transp lantation22risks and benefits [ J ] 1Transp lant Proc, 2002, 34 ( 2 ) :56025631
[ 31 ]Woodle ES,Vincenti F, LorberMI, et al1A multicenter p ilot study of early ( 42day ) steroid cessation in renal transp lant recip ients under simulect, tacrolimus and sirolimus [ J ] 1Am J Transp lant, 2005, 5 ( 1 ) :15721661
[ 32 ]Woodle ES1A p rospective, randomized, multicenter, double2blind study of early corticosteroid cessation versus long2term maintenance of cortico steroid therapy with tacrolimus and mycophenolate mofetil in p rimary renal transp lant recip ients: one year report[ J ]1Transp lant Proc, 2005, 37(2) : 80428081
[ 33 ]Kasiske BL, Chakkera HA, Louis TA, et al1A meta2analysis of immunosupp ression withdrawal trials in renal transp lantation [ J ] 1J Am SocNephrol, 2000, 11 (10) : 1910219171
[ 34 ] Stallone G, Di PS, Schena A, et al1Early withdrawal of cyclosporine Aimp roves 12year kidney graft structure and function in sirolimus2treated patients[ J ]1Transp lantation, 2003, 75 (7) : 998210031
[ 35 ]陈江华,王仁定,吴建永1供体骨髓输注肾移植受者外周血嵌合体动态变化及对排斥的影响[ J ]1中华肾脏病杂志, 2003, 19 ( 6) : 38523881
[ 36 ] Scandling JD,Busque S,Dejbakhsh JS, et al1Tolerance and chimerism after renal and hematopoietic2cell transp lantation[ J ]1N Engl JMed, 2008,358 (4) : 36223681
[ 37 ] J ian2yongWu, J iang2hua Chen, Yi2mingWang, et al1 Imp roved Clinical Outcomes in Chinese Renal Allograft Recip ients Receiving Lower Dose Immunosupp ressants[ J ]1Transp lantation, 2004, 78: 71327181