Transplantation Research Immunology Group, University of Oxford, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK.
Atherosclerosis. 2012 Aug;223(2):291-8. doi: 10.1016/j.atherosclerosis.2012.05.010. Epub 2012 May 19.
Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions.
We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development.
In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts.
Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients.
移植性动脉硬化（TA）限制了心脏移植受者的长期存活。虽然单核细胞/巨噬细胞在原发性动脉粥样硬化中的作用已得到充分证实，但在 TA 中的研究要少得多。血浆胆固醇是 TA 发展的最重要的非免疫危险因素，但潜在机制在很大程度上尚不清楚。我们假设，在高脂血症条件下，单核细胞/巨噬细胞可能在 TA 的发病机制中发挥重要作用。
我们研究了在高脂血症 ApoE（-/-）受体中与野生型对照相比，完全错配的动脉同种异体移植物中的 TA。通过体内荧光微球标记跟踪不同单核细胞群在移植物中的募集。我们使用抗体介导的耗竭方案来剖析 T 淋巴细胞和单核细胞对疾病发展的相对贡献。
在高脂血症环境中，TA 的进展高度加剧，炎症性 CD11b（+）CD115（+）Ly-6C（hi）单核细胞优先募集到内膜。移植部位巨噬细胞源性泡沫细胞的数量与血浆胆固醇和疾病严重程度密切相关。耗竭 Ly-6C（hi）单核细胞和嗜中性粒细胞可显著抑制巨噬细胞积聚和疾病进展。加速的单核细胞募集是通过 T 细胞非依赖性机制发生的，因为 T 细胞耗竭不会影响巨噬细胞在移植物中的积累。
我们的研究首次确定了炎症性 Ly-6C（hi）单核细胞参与 TA 的发病机制，特别是在高脂血症的情况下。靶向调节这些细胞募集和激活的治疗方法可能延迟冠状动脉同种异体移植血管病并改善心脏移植受者的长期存活。
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