Department of Surgery, University of Cambridge, Cambridge, UK.
Department of Surgery, University of Cambridge, Cambridge, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S18. doi: 10.1016/S0140-6736(15)60333-6.
Memory T cells are known to reside in peripheral non-lymphoid tissue, but how their presence within solid organ allografts affects transplant outcomes is not known. We have previously described how graft-versus-host (GVH) allorecognition by passenger CD4 T cells within MHC class II-mismatched bm12 heart grafts provokes antinuclear humoral autoimmunity in C57BL/6 recipient mice. Here we aimed to examine how such GVH recognition affects the alloresponse to allografts with greater mismatching.
A MHC class I and II mismatched murine model of cardiac transplantation was developed (bm12.Kd.IE to C57BL/6). After transplantation, cellular and humoral responses against mismatched antigens were measured with ELISPOT and ELISA, and the effect of GVH recognition assessed by depletion of donor CD4 T cells before graft procurement. Antinuclear autoantibody development was assessedwith HeP-2 indirect immunofluorescence. The role of recipient natural killer (NK) cells was examined by depletion with anti-NK1.1 antibody.
Bm12.Kd.IE heart grafts provoked strong germinal centre alloantibody and autoantibody responses in C57BL/6 recipients and developed allograft vasculopathy. By contrast, heart grafts from CD4 T-cell-depleted donors developed only minimal vasculopathy, and the alloantibody responses were weaker, without observable autoantibody. Bm12.Kd.IE CD4 T cells survived long term when transferred to RAG hosts suggesting that avoidance of killing by host NK cells might be essential for autoantibody development. In support, in a model of alloantibody-mediated vasculopathy, depletion of NK cells from a C57BL/6 recipient of a BALB/c heart graft resulted in the development of autoantibody, amplification of the alloantibody response, and rapid allograft rejection. This amplification was abrogated by depletion of donor CD4 T cells.
Although host adaptive immunity is expected to bring about destruction of passenger lymphocytes within heart allografts, this process occurs too slowly to prevent GVH-mediated augmentation of the alloresponse to the graft. Rather, rapid killing of donor lymphocytes by host alloreactive NK cells is essential. Passenger CD4 lymphocytes might therefore contribute to chronic rejection in recipients receiving an allograft that does not prompt innate NK cell recognition.
Wellcome Trust Clinical Research Training Fellowship.
已知记忆 T 细胞存在于外周非淋巴组织中，但它们在实体器官同种异体移植物中的存在如何影响移植结果尚不清楚。我们之前描述了 MHC Ⅱ类错配 bm12 心脏移植物中过客 CD4 T 细胞的移植物抗宿主（GVH）识别如何引发 C57BL/6 受体小鼠的抗核体液自身免疫。在这里，我们旨在研究这种 GVH 识别如何影响对具有更大错配的同种异体移植物的同种异体反应。
开发了一种 MHC Ⅰ和Ⅱ类错配的心脏移植鼠模型（bm12.Kd.IE 至 C57BL/6）。移植后，通过 ELISPOT 和 ELISA 测量针对错配抗原的细胞和体液反应，并通过在移植物获取前耗尽供体 CD4 T 细胞来评估 GVH 识别的影响。通过 Hep-2 间接免疫荧光评估抗核自身抗体的发展。通过用抗 NK1.1 抗体耗尽受体自然杀伤（NK）细胞来研究 NK 细胞的作用。
bm12.Kd.IE 心脏移植物在 C57BL/6 受体中引发强烈的生发中心同种异体抗体和自身抗体反应，并发展为同种异体移植物血管病。相比之下，来自耗尽 CD4 T 细胞的供体的心脏移植物仅发展出最小的血管病变，同种异体抗体反应较弱，没有观察到自身抗体。bm12.Kd.IE CD4 T 细胞在转移到 RAG 宿主时可以长期存活，这表明避免宿主 NK 细胞的杀伤可能是自身抗体发展所必需的。支持这一观点的是，在同种抗体介导的血管病模型中，从 BALB/c 心脏移植物的 C57BL/6 受体中耗尽 NK 细胞导致自身抗体的发展、同种异体抗体反应的放大和同种异体移植物的快速排斥。通过耗尽供体 CD4 T 细胞可以消除这种放大。
尽管宿主适应性免疫预期会导致心脏同种异体移植物内过客淋巴细胞的破坏，但这一过程发生得太慢，无法阻止 GVH 介导的同种异体移植物反应的增强。相反，宿主同种反应性 NK 细胞对供体细胞的快速杀伤是至关重要的。因此，在接受不会引起固有 NK 细胞识别的同种异体移植物的受体中，过客 CD4 淋巴细胞可能有助于慢性排斥反应。
惠康信托临床研究培训奖学金。
