Department of Surgery, University of Cambridge, Cambridge, UK.
Department of Surgery, University of Cambridge, Cambridge, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S17. doi: 10.1016/S0140-6736(15)60332-4.
Uniquely, alloantigen is recognised by two pathways: as intact antigen on the surface of donor antigen-presenting cells (direct) and as self-restricted processed allopeptide (indirect). The indirect pathway is believed to be longlasting, and is generally considered to be a single entity. Here we address how indirect responses against different alloantigens differ in their strength and longevity, and how this knowledge could be used to direct immunoregulatory therapy with antigen-specific regulatory T cells (Tregs).
A murine model of cardiac transplantation was used (bm12.Kd.IE to C57BL/6). Indirect CD4 T-cell allorecognition of mismatched donor MHC class I and II, and of H-Y minor histocompatibility antigen was assessed by quantifying proliferation of adoptively transferred monoclonal T-cell receptor transgenic T cells (TCR75, Tea, Mar). Antigen presentation by dendritic cells and B cells was assessed by selective depletion with diphtheria toxin or depleting anti-CD20 monoclonal antibody. Tregs were generated by in-vitro culture.
Indirect pathway responses were heterogeneous. Whereas the indirect response against class I alloantigen was longlasting and persistently strong, the response against class II alloantigen decayed within 2 weeks. Leucocyte depletion studies confirmed that this difference was due to rapid destruction of MHC class II expressing donor B cells and dendritic cells in the recipient, whereas anti-class I responses were generated by continual processing of graft parenchymal cells; recognition of donor haemopoietic fraction was not required. Notably, transfer of MHC class I specific Tregs at transplant or 3 weeks later abrogated germinal centre alloantibody responses and blocked development of allograft vasculopathy, whereas class II specific Tregs were ineffective when transferred at the late timepoint.
Although indirect allorecognition is considered to be a single entity, our results show that it consists of a number of responses that vary in duration and strength according to target alloantigen. The ability of class I allopeptide specific Tregs, but not class II specific Tregs, to prevent rejection when transferred at a late timepoint suggests that antigen-specific targeting of dominant and longlasting pathways might be particularly effective at preventing chronic rejection.
Wellcome Trust Clinical Research Training Fellowship.
同种异体抗原通过两种途径被识别：供体抗原呈递细胞表面的完整抗原（直接途径）和自身限制性加工的同种异体肽（间接途径）。间接途径被认为是持久的，通常被认为是一个单一的实体。在这里，我们研究了针对不同同种异体抗原的间接反应在强度和持久性上的差异，以及如何利用这些知识指导针对抗原特异性调节性 T 细胞（Treg）的免疫调节治疗。
使用了心脏移植的小鼠模型（bm12.Kd.IE 到 C57BL/6）。通过定量分析过继转移的单克隆 T 细胞受体转基因 T 细胞（TCR75、Tea、Mar）的增殖，评估了对 mismatched 供体 MHC Ⅰ类和Ⅱ类以及 H-Y 次要组织相容性抗原的间接 CD4 T 细胞同种异体识别。通过使用白喉毒素或耗尽抗 CD20 单克隆抗体选择性耗尽树突状细胞和 B 细胞来评估抗原呈递。通过体外培养生成 Treg。
间接途径反应具有异质性。尽管针对Ⅰ类同种异体抗原的间接反应是持久且持续强烈的，但针对Ⅱ类同种异体抗原的反应在 2 周内就衰减了。白细胞耗竭研究证实，这种差异是由于受体中 MHC Ⅱ类表达的供体 B 细胞和树突状细胞的快速破坏所致，而针对Ⅰ类的反应则是由移植物实质细胞的连续加工产生的；不需要识别供体造血部分。值得注意的是，在移植时或 3 周后转移 MHC Ⅰ类特异性 Treg 可消除生发中心同种异体抗体反应并阻止移植物血管病变的发展，而在晚期转移时，Ⅱ类特异性 Treg 则无效。
尽管间接同种异体识别被认为是一个单一的实体，但我们的结果表明，它由多种反应组成，这些反应根据靶同种异体抗原的不同而在持续时间和强度上有所不同。在晚期转移时，Ⅰ类同种异体肽特异性 Treg 而不是Ⅱ类特异性 Treg 具有预防排斥的能力，这表明针对主要和持久途径的抗原特异性靶向可能特别有效地预防慢性排斥。
惠康信托临床研究培训奖学金。
