基于CTLA4-Ig的预处理方案诱导对心脏同种异体移植物的耐受。

CTLA4-Ig-based conditioning regimen to induce tolerance to cardiac allografts.

作者信息

Li Sen, Salgar Shashikumar K, Thanikachalam Mohan, Murdock Alan D, Gammie James S, Demetris Anthony J, Zeevi Adriana, Pham Si M

机构信息

Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, Florida 33156, USA.

出版信息

J Surg Res. 2006 Dec;136(2):238-46. doi: 10.1016/j.jss.2006.05.032. Epub 2006 Oct 13.

DOI:10.1016/j.jss.2006.05.032

PMID:17046021

Abstract

BACKGROUND

Transplant rejection and toxicity associated with chronic immunosuppressive therapy remain a major problem. Mixed hematopoietic chimerism has been shown to produce tolerance to solid organ transplants. However, currently available protocols to induce mixed hematopoietic chimerism invariably require toxic pre-conditioning. In this study, we investigated a non-toxic CTLA4-Ig-based protocol to induce donor-specific tolerance to cardiac allografts in rats.

METHODS

Fully mismatched, 4 to 6 week old ACI (RT1.A(a)) and Wistar Furth (RT1.A(u)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with CTLA4-Ig 2 mg/kg/day (on days 0, 2, 4, 6, 8), tacrolimus 1 mg/kg/day (daily, from days 0 to 9), and a single dose of anti-lymphocyte serum (10 mg) on day 10, soon after total body irradiation (300 cGy) and donor bone marrow (100 x 10(6) T-cell depleted cells) transplantation (BMT). Six weeks after BMT, chimeric animals received heterotopic heart transplants.

RESULTS

Hematopoietic chimerism was 18.8 +/- 10.6% at day 30, and was stable (24 +/- 10%) at 1 year post-BMT; there was no graft versus host disease. Chimeric recipients (RT1.A(u)) permanently accepted (>360 days) donor-specific (RT1.A(a); n = 6) hearts, yet rapidly rejected (<9 days) third-party hearts (RT1.A(l); n = 5). Graft (heart) tolerant (>100 days) recipients accepted donor-specific secondary skin grafts (>200 days) while rejected the third-party skin grafts (<9 days). Lymphocytes of graft tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection.

CONCLUSIONS

The CTLA4-Ig based conditioning regimen with donor BMT produced mixed chimerism and induced donor- specific tolerance to cardiac allografts.

摘要

背景

移植排斥反应以及与慢性免疫抑制治疗相关的毒性仍然是一个主要问题。混合造血嵌合体已被证明可产生对实体器官移植的耐受性。然而，目前用于诱导混合造血嵌合体的方案总是需要毒性预处理。在本研究中，我们研究了一种基于无毒CTLA4-Ig的方案，以诱导大鼠对心脏同种异体移植产生供体特异性耐受性。

方法

将完全不匹配的4至6周龄ACI（RT1.A(a)）和Wistar Furth（RT1.A(u)）大鼠分别用作细胞/器官供体和受体。受体在全身照射（300 cGy）和供体骨髓（100×10⁶个去除T细胞的细胞）移植（BMT）后不久，于第0、2、4、6、8天接受2 mg/kg/天的CTLA4-Ig治疗，第0至9天每天接受1 mg/kg/天的他克莫司治疗，并在第10天接受单剂量抗淋巴细胞血清（10 mg）治疗。BMT后6周，嵌合动物接受异位心脏移植。

结果

BMT后第30天造血嵌合体为18.8±10.6%，BMT后1年时稳定（24±10%）；未出现移植物抗宿主病。嵌合受体（RT1.A(u)）永久性接受（>360天）供体特异性（RT1.A(a)；n = 6）心脏，但迅速排斥（<9天）第三方心脏（RT1.A(l)；n = 5）。移植（心脏）耐受（>100天）的受体接受供体特异性二次皮肤移植（>200天），同时排斥第三方皮肤移植（<9天）。移植耐受动物的淋巴细胞在混合淋巴细胞培养中以供体特异性方式表现出低反应性。耐受移植的组织学显示无闭塞性动脉病或慢性排斥反应。