Induction of donor-specific tolerance by adenovirus-mediated cd40ig gene therapy in rat liver transplantation1
Induction of donor-specific tolerance by adenovirus-mediated cd40ig gene therapy in rat liver transplantation1
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腺病毒介导的 cd40ig 基因治疗在大鼠肝移植中诱导供者特异性耐受1
作者：
M. Nomura;K. Yamashita;M. Murakami;M. Takehara;H. Echizenya;M. Sunahara;N. Kitagawa;M. Fujita;H. Furukawa;T. Uede;S. Todo
背景。抗CD154抗体（Ab）阻断CD40-CD40配体（CD154）共刺激途径延长同种异体器官移植存活然而，需要反复给药以提供足够的免疫抑制。为了寻找一种简单有效的方法来干扰这一信号，我们通过编码CD40Ig基因（AdCD40Ig）应用腺病毒介导的基因治疗。方法。将ACI （RT1av1）大鼠肝移植物原位移植至LEW （rt11）大鼠体内，移植后即刻经阴茎静脉给予AdCD40Ig （n=6）。结果。AdCD40Ig单次处理1×109斑块形成单位诱导CD40Ig基因在同种异体移植物肝脏上特异性表达，在血清中产生大量蛋白质，并允许移植物无限期存活。然而，未给予治疗或对照腺病毒载体（AdLacZ）的LEW受体迅速排斥ACI肝。此外，adcd40ig治疗的长期幸存者接受了来自供体株的皮肤移植，而不是第三方移植。组织病理学检查显示，长期存活动物的肝脏结构完全保持正常，无单核细胞浸润。结论。通过CD40Ig基因治疗阻断CD40-CD154通路是一种有效的同种异体抗原特异性免疫抑制策略，可诱导同种异体肝移植永久接受，可能成为临床肝移植的一种新的治疗候选方法。
Background. Blockade of CD40-CD40 ligand (CD154) costimulatory pathway with anti-CD154 antibody (Ab) prolongs allograft survival in experimental organ transplantations; however, repeated agent administration is needed to provide an adequate immunosuppression. Seeking for simple and effective approach to interfere this signaling, we applied adenovirus-mediated gene therapy by encoding CD40Ig gene (AdCD40Ig). Methods. Liver graft from ACI (RT1av1) rat was transplanted orthotopically into LEW (RT1l) rat, and AdCD40Ig was given to animals via the penile vein immediately after grafting (n=6). Results. A single treatment with AdCD40Ig at 1×109 plaque forming units induced specific expression of CD40Ig gene on allograft liver, produced substantial amount of the protein in the sera, and allowed indefinite graft survival. Whereas, LEW recipients given no treatment or control adenovirus vector (AdLacZ) promptly rejected ACI liver. In addition, AdCD40Ig-treated, long-term survivors accepted skin graft from the donor strain but not the third party graft. Histopathology revealed that liver structure of the long-term surviving animals was completely preserved in normal with no infiltration of mononuclear cells. Conclusion. Blockade of CD40-CD154 pathway by CD40Ig gene therapy is a potent alloantigen-specific immunosuppressive strategy to induce permanent acceptance of liver allograft and would be a new therapeutic candidate in a clinical liver transplantation.
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通过 ANTI-CD40 配体 (CD154) 抗体治疗延长灵长类同种异体心脏移植物的存活。
影响因子：
6.2
作者：
Pierson3rd,RN;Chang,AC;Blum,MG;Blair,KS;Scott,MA;Atkinson,JB;Collins,BJ;Zhang,JP;Thomas,DW;Burkly,LC;Miller,GG
通讯作者：
Miller,GG
DOI：
10.1073/pnas.92.21.9560
发表时间：
1995-10-10
影响因子：
11.1
作者：
PARKER, DC;GREINER, DL;ROSSINI, AA
通讯作者：
ROSSINI, AA
DOI：
10.1073/pnas.91.10.4407
发表时间：
1994-05-10
影响因子：
11.1
作者：
YANG, YP;NUNES, FA;WILSON, JM
通讯作者：
WILSON, JM
DOI：
10.1073/pnas.93.24.13967
发表时间：
1996-11-26
影响因子：
11.1
作者：
Hancock, WW;Sayegh, MH;Turka, LA
通讯作者：
Turka, LA
DOI：
10.1073/pnas.96.14.8132
发表时间：
1999-07-06
影响因子：
11.1
作者：
Kenyon, NS;Chatzipetrou, M;Ricordi, C
通讯作者：
Ricordi, C