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Induction of donor-specific tolerance with splenocytes-for clinical application to organ transplantation

诱导脾细胞供者特异性耐受——用于器官移植的临床应用

基本信息

批准号：
12671137
负责人：
NARUMI Shunji
金额：
$ 1.73万
依托单位：
Hirosaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Allogeneic chimerism has been established in the graft-accepting recipients and the donor cells in the host may act in a major role to facilitate the induction of tolerance. In the present study, we investigated effects of allogeneic splenocytes (SPLCs) mixture, which we usually procure at cadaveric organ donor surgery, to the bone marrow cells on the tolerance induction.1) Injection of 3x10^6 BMCs did not establish effective mixed chimerism. Donor cells were completely rejected by single 10x10^6 SPLCs injection. In a group of a mixture of very low dose of 3x10^6 BMCs and 10x10^6 SPLCs, however, mice were successfully induced chimerism. These chimeric mice showed donor-specific tolerance in vivo; skin grafting. T-cell enriched SPLCs could induce effective chimerism when mixed with a small amount of BMCs, but a mixture of B-cell enrich population of SPLCs and BMCs failed to establish effective chimerism. SPLCs without macrophages were as effective as naive SPLCs to induce tolerance. Even low dose of BMCs can establish a state of allogeneic chimerism and donor specific tolerance if combined with vigorous SPLCs. T-cells in SPLCs may play a important role to support BMCs for induction of donor-specific tolerance.2) Efficacy of a donor splenocytes mixed with stem cells in the peripheral blood were also investigated. Granulocyte stimulating factor was given and stem cell from peripheral blood was examined. Effective chimerism was established with a low dose of stem cell with a mixture of splenocytes. This results indicates the possibility of clinical usage of a chimerism induction because of safe procurement of stem cell in PBL instead of bone marrow cells.3) GVHD remains as a great concern. T-cells may play a major role for GVHD, however, they do for establishment of chimerism. It is necessary to establish a method to prevent GVHD without eliminating T-cells.

在接受移植物的受者中已经建立了异基因嵌合体，宿主中的供体细胞可能在促进耐受的诱导中起主要作用。在本研究中，我们研究了同种异体脾细胞（SPLCs）混合物，我们通常在尸体器官供体手术中获得，对骨髓细胞的耐受诱导的影响。1）注射3 × 10^6个BMCs没有建立有效的混合嵌合体。供体细胞通过单次10 × 10^6 SPLCs注射被完全排斥。然而，在一组极低剂量的3 × 10^6个BMC和10 × 10^6个SPLCs的混合物中，小鼠成功诱导了嵌合体。这些嵌合小鼠在体内表现出供体特异性耐受性;皮肤移植。当与少量BMCs混合时，富含T细胞的SPLCs可以诱导有效的嵌合，但是富含B细胞的SPLCs和BMCs的混合物不能建立有效的嵌合。没有巨噬细胞的SPLCs与幼稚SPLCs一样有效地诱导耐受。即使低剂量的BMCs也可以建立同种异体嵌合状态和供体特异性耐受，如果与强有力的SPLCs组合。SPLCs中的T细胞可能在支持BMCs诱导供体特异性耐受中起重要作用。2）还研究了供体脾细胞与外周血干细胞混合的功效。给予粒细胞刺激因子，并检查外周血干细胞。用低剂量的干细胞与脾细胞的混合物建立了有效的嵌合体。这一结果表明，由于在PBL中安全地获得干细胞而不是骨髓细胞，嵌合体诱导的临床应用是可能的。3）GVHD仍然是一个很大的关注。T细胞可能在GVHD中起主要作用，然而，它们在嵌合体的建立中起主要作用。因此，有必要建立一种在不清除T细胞的情况下预防GVHD的方法。