先天性和获得性免疫机制在临床肠道移植排斥反应中的作用。

Role of innate and acquired immune mechanisms in clinical intestinal transplant rejection.

作者信息

Mathew James M, Tryphonopoulos Panagiotis, DeFaria Werviston, Ruiz Phillip, Miller Joshua, Barrett Terrence A, Tzakis Andreas G, Kato Tomoaki

机构信息

1 Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL. 2 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL. 3 Jesse Brown VA Medical Center, Chicago, IL. 4 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL. 5 Department of Microbiology-Immunology, University of Miami Miller School of Medicine, Miami, FL. 6 Miami VA Medical Center, Miami, FL. 7 Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL.

出版信息

Transplantation. 2015 Jun;99(6):1273-81. doi: 10.1097/TP.0000000000000491.

DOI:10.1097/TP.0000000000000491

PMID:25539468

Abstract

BACKGROUND

Long-term outcomes of intestinal transplantation are limited by infection and rejection. To understand the underlying immune mechanisms, graft infiltrating and peripheral blood cells were analyzed using multiple ex vivo assays in intestinal transplantation recipients.

METHODS

Infiltrating cells from rejected (graft enterectomy for rejection) and accepted or quiescent (stoma closure in stable transplant recipients) grafts were isolated and phenotypically characterized as to subsets and Toll-like receptor expressions as well as functionally tested for antimicrobial and antidonor immune responses. Multiparameter antidonor immunity was also assessed serially in the peripheral blood.

RESULTS

The graft infiltrating lymphocytes were mostly of recipient origin in all patients tested. In rejecting grafts, the predominant populations were TcRαβ(+)CD3(+)CD8(+) T cells, and CD14(+) monocytes that coexpressed Toll-like receptor-2, receptor-3, receptor-4, receptor-5, and receptor-9, suggesting innate immune activation. In quiescent allografts the major cell subsets were CD13(+)CD14(-) monocytes and CD4(+)CD25(+) T cells with possible regulatory functions. Infiltrating cells from rejected but not quiescent grafts proliferated in response to enteric bacterial and donor antigens as well as killed donor targets. Serial follow-up of peripheral blood indicated donor-specific posttransplant unresponsiveness in micro-cell-mediated lympholysis (m-CML) and mixed lymphocyte reaction (MLR) in recipients with quiescent grafts, but not in recipients with multiple rejection episodes. Enzyme-Linked ImmunoSpot assays yielded parallel results: granzyme-B with micro-cell-mediated lympholysis and interferon-γ with MLR tests.

CONCLUSION

These results were consistent with the notion that rejection was associated with innate and acquired antimicrobial and antidonor immune reactivity and that patients with stable grafts were free from these deleterious effects.

摘要

背景

肠道移植的长期预后受感染和排斥反应的限制。为了解潜在的免疫机制，我们使用多种体外试验对肠道移植受者的移植物浸润细胞和外周血细胞进行了分析。

方法

从排斥的移植物（因排斥反应而行移植物肠切除术）以及接受或静止的移植物（稳定移植受者的造口关闭）中分离浸润细胞，对其亚群、Toll样受体表达进行表型特征分析，并对抗菌和抗供体免疫反应进行功能测试。还对外周血中的多参数抗供体免疫进行了连续评估。

结果

在所有测试患者中，移植物浸润淋巴细胞大多来源于受者。在发生排斥反应的移植物中，主要群体是TcRαβ(+)CD3(+)CD8(+) T细胞以及共表达Toll样受体-2、受体-3、受体-4、受体-5和受体-9的CD14(+)单核细胞，提示固有免疫激活。在静止的同种异体移植物中，主要细胞亚群是可能具有调节功能的CD13(+)CD14(-)单核细胞和CD4(+)CD25(+) T细胞。来自排斥但非静止移植物的浸润细胞对肠道细菌和供体抗原产生增殖反应，并杀死供体靶细胞。外周血的连续随访表明，静止移植物受者在微细胞介导的淋巴细胞溶解（m-CML）和混合淋巴细胞反应（MLR）中出现移植后供体特异性无反应性，但在多次发生排斥反应的受者中未出现。酶联免疫斑点试验得出了类似结果：m-CML检测中为颗粒酶-B，MLR检测中为干扰素-γ。