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Approaches to the clinical application of donor-specific tolerance in living donor organ transplantation.

供者特异性耐受在活体器官移植中的临床应用方法。

基本信息

批准号：
14207049
负责人：
KITAJIMA Masaki
金额：
$ 32.61万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

(1)Alloantigen or allopeptide can induce hyporesponsiveness to fully mismatched cardiac allografts when delivered intratracheally or orally.(2)Alloantigen or allopeptide can generate regulatory cells when delivered intratracheally.(3)The population of regulatory cells contains regulatory T cells and regulatory dendritic cells.(4)The regulatory T cells and regulatory dendritic cells can suppress rejection of allogeneic heart grafts.(5)The suppression by regulatory T cells and regulatory dendritic cells is donor specific.(6)Intratracheal delivery of alloantigen combined with anti-CD4 mAb or anti-CD40L mAb induces operational tolerance to fully allogeneic cardiac allografts.(7)CD80/86 pathway, signals of THF-family and PD-1 signal are necessary for induction of regulatory cells by intratracheal delivery of alloantigen, individually.(8)IL-10 is essential for induction of regulatory cells by intratracheal delivery of alloantigen.(9)Mycophenolate mofetil and Rapamycin work synergistically for induction of regulatory cells, although high dose of Tacrolimus, Azathioprine and Cyclosporine prevent generating regulatory cells.(10)Histamine 2 receptor antagonist, serotonin receptor antagonist, ursodeoxycholic acid, MCI-186 (free radical scavenger) and anti-thrombin III can generate regulatory cells.(11)The fraction of regulatory T cells is CD4^+CD25^+CTLA4^+ in our model.(12)The number of CD4^+CD25^+CTLA4^+ cells decreased before rejection episode in preliminary clinical study.

（1）同种异体抗原或同种异体肽经气管内或口服给药可诱导对完全不匹配的同种异体心脏移植物的低反应性。（2）同种异体抗原或同种异体肽经血管内给药可产生调节细胞。（3）调节性细胞群含有调节性T细胞和调节性树突细胞。（4）调节性T细胞和调节性树突状细胞可抑制同种异体心脏移植排斥反应。（5）调节性T细胞和调节性树突细胞的抑制是供体特异性的。（6）同种异体抗原联合抗CD 4 mAb或抗CD 40 L mAb的腔内递送诱导了对完全同种异体心脏移植物的手术耐受。（7）CD 80/86通路、THF-family信号和PD-1信号是同种异体抗原诱导调节性细胞的必要信号。（8）IL-10对同种异体抗原的腔内递送诱导调节细胞的形成是必需的。（9）霉酚酸酯和雷帕霉素协同诱导调节性细胞的产生，尽管高剂量的他克莫司、硫唑嘌呤和环孢霉素阻止调节性细胞的产生。（10）组胺2受体拮抗剂、5-羟色胺受体拮抗剂、熊去氧胆酸、MCI-186（自由基清除剂）和抗凝血酶III可产生调节细胞。（11）在我们的模型中，调节性T细胞的比例为CD 4 ^+ CD 25 ^+ CTLA 4 ^+。（12）临床初步研究表明，在排斥反应发生前，CD 4 ^+ CD 25 ^+ CTLA 4 ^+细胞数量减少。