FTY720与共刺激阻断对肠道同种异体移植排斥反应的控制

Control of intestinal allograft rejection by FTY720 and costimulation blockade.

作者信息

Yan S, Rodriguez-Barbosa J I, Pabst O, Beckmann J H, Brinkmann V, Förster R, Hoffmann M W

机构信息

Medical School of Hannover, Hannover, Germany.

出版信息

Transplant Proc. 2005 Jan-Feb;37(1):114-5. doi: 10.1016/j.transproceed.2004.12.089.

DOI:10.1016/j.transproceed.2004.12.089

PMID:15808565

Abstract

INTRODUCTION

The clinical application of small bowel transplantation (SBTx) is hampered by its pronounced immunogenicity. In this study we examined the effects of the novel immunosuppressant FTY720 and costimulation blockade by an anti-CD40L mAb (MR-1) in a stringent mouse model of SBTx.

METHODS

SBTx was performed in mice with a full MHC mismatch (donors: C3H=H-2(k); recipients: C57BL/6=H-2(b)). Recipients were divided into four groups: 1, untreated group; 2, MR1 monotherapy (500 microg IV on days 0, 2, 4, and 7); 3, FTY720 monotherapy (1 mg/kg body weight PO for 14 consecutive days after transplantation); 4, FTY720 plus MR1-treated group. Graft rejection grades were assessed by H&E staining. Graft mesenteric lymph nodes (MLNs), Peyer's patches (PPs), as well as intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) were analyzed by flow cytometry and three-color immunofluorescence staining.

RESULTS

Neither FTY720 nor MR1 monotherapy was efficient in preventing the rejection of mouse intestinal allografts, whereas FTY720 plus MR1 profoundly inhibited the rejection response at the 14th posttransplant day. The infiltration of host lymphocytes was reduced in graft MLNs, PPs, IELs, and LPLs by FTY720 therapy. FTY720 plus MR1 inhibited host CD8(+) T-cell infiltration in graft LPLs when compared with grafts treated with FTY720 only. Additionally, two subpopulations, CD11b(+high) Gr1(-) and CD11b(+intermediate) Gr1(+) cells, were decreased in FTY720-treated grafts.

CONCLUSIONS

FTY720 plus MR1 efficiently delayed intestinal allograft rejection in a mouse model by preventing the infiltration of host lymphocytes, particularly of CD8(+) cells.

摘要

引言

小肠移植（SBTx）的临床应用因其显著的免疫原性而受到阻碍。在本研究中，我们在严格的小鼠SBTx模型中研究了新型免疫抑制剂FTY720和抗CD40L单克隆抗体（MR-1）共刺激阻断的作用。

方法

在完全MHC不匹配的小鼠中进行SBTx（供体：C3H = H-2(k)；受体：C57BL/6 = H-2(b)）。受体分为四组：1，未治疗组；2，MR1单药治疗组（在第0、2、4和7天静脉注射500微克）；3，FTY720单药治疗组（移植后连续14天口服1毫克/千克体重）；4，FTY720加MR1治疗组。通过苏木精和伊红染色评估移植物排斥等级。通过流式细胞术和三色免疫荧光染色分析移植物肠系膜淋巴结（MLN）、派尔集合淋巴结（PP）以及上皮内淋巴细胞（IEL）和固有层淋巴细胞（LPL）。

结果

FTY720和MR1单药治疗均不能有效预防小鼠小肠同种异体移植物的排斥反应，而FTY720加MR1在移植后第14天显著抑制了排斥反应。FTY720治疗可减少移植物MLN、PP、IEL和LPL中宿主淋巴细胞的浸润。与仅用FTY720治疗的移植物相比，FTY720加MR1抑制了宿主CD8(+) T细胞在移植物LPL中的浸润。此外，在FTY720治疗的移植物中，两个亚群CD11b(+高) Gr1(-)和CD11b(+中等) Gr1(+)细胞减少。