Buckland Matthew, Lombardi Giovanna
Immunoregulation Laboratory, Department of Nephrology, Thomas Guy House, Guys Hospital Campus, Kings College London School of Medicine, Guys, Kings College and St Thomas Hospitals, London SE1 9RT, UK.
Handb Exp Pharmacol. 2009(188):197-213. doi: 10.1007/978-3-540-71029-5_9.
Tolerance is maintained by central and peripheral regulatory mechanisms and is essential to prevent autoimmunity. In the setting of solid organ or haematopoietic transplantation, the indirect pathway of allorecognition is a significant driver of chronic rejection. Chronic rejection proceeds despite effective immunosuppressive therapy, therefore achieving immunological tolerance to control the indirect pathway is a desirable goal. Tolerance induction may be achieved by vaccination with modified antigen presenting cells (APCs). Mature dendritic cells (DCs) are potent APCs, but immature DCs have been shown to have a reduced allo-stimulatory capacity and can be tolerogenic. Drug treatment has been shown to decrease the allo-stimulatory capacity of DC compared to immature DC. Dexamethasone and vitamin D3 have been established as having potent effects on dendritic cell immunogenicity.The effects of aspirin, a non-steroidal anti-inflammatory, on DCs have not previously been so extensively studied and here we will review the work which has been carried out using aspirin to induce tolerogenic DCs.We have examined the mechanisms of tolerance induction using human DCs and T cells. It has been possible to demonstrate that in aspirin treated, human DCs there is inhibition of the nuclear factor K-B (NFKB) signalling pathway, modified cytokine production, reduced expression of co-stimulatory molecules (CD40, CD80, and CD86) and increased expression of immunoglobulin-like transcript-3 (ILT3). The decreased expression of co-stimulatory molecules is maintained following cytokine or lipopolysaccharide (LPS) challenge. Drug treatment of DCs increases the expression of immunoglobulin-like transcript 3 (ILT3) when compared with immature DCs (iDCs), and these high levels of expression are maintained when the cells are challenged with a maturational stimulus. Aspirin also reduces the allo-stimulatory capacity of human DCs, and induces hypo-responsiveness and regulatory activity in responder T cells. These regulatory T-cells were CD4(+) CD25(+) FOXP3(+) and by studying CD25(-) or CD45RA populations, it was possible to determine that these regulatory T cells were generated de novo rather than requiring the expansion of naturally occurring Tregs. Aspirin continues therefore to be of interest with regard its wider effects on immune regulation, other than that mediated by direct inhibition of cyclo-oxygenase, in particular its ability to induce tolerogenic DCs at therapeutic concentrations in humans.
耐受性由中枢和外周调节机制维持，对于预防自身免疫至关重要。在实体器官或造血移植的情况下，同种异体识别的间接途径是慢性排斥反应的重要驱动因素。尽管有有效的免疫抑制治疗，慢性排斥反应仍会发生，因此实现免疫耐受以控制间接途径是一个理想的目标。通过用修饰的抗原呈递细胞（APC）进行疫苗接种可以实现耐受性诱导。成熟的树突状细胞（DC）是强大的APC，但已证明未成熟的DC具有降低的同种异体刺激能力，并且可以具有耐受性。与未成熟的DC相比，药物治疗已显示可降低DC的同种异体刺激能力。地塞米松和维生素D3已被证实对树突状细胞的免疫原性有强大作用。阿司匹林作为一种非甾体抗炎药，对DC的作用以前尚未得到如此广泛的研究，在这里我们将回顾使用阿司匹林诱导耐受性DC的相关工作。我们已经研究了使用人DC和T细胞诱导耐受性的机制。已经能够证明，在阿司匹林处理的人DC中，核因子κB（NFKB）信号通路受到抑制，细胞因子产生改变，共刺激分子（CD40、CD80和CD86）的表达降低，免疫球蛋白样转录物3（ILT3）的表达增加。在细胞因子或脂多糖（LPS）刺激后，共刺激分子的表达降低得以维持。与未成熟DC（iDC）相比，对DC进行药物治疗可增加免疫球蛋白样转录物3（ILT3）的表达，并且当细胞受到成熟刺激时，这些高水平的表达得以维持。阿司匹林还降低了人DC的同种异体刺激能力，并在反应性T细胞中诱导低反应性和调节活性。这些调节性T细胞是CD4(+) CD25(+) FOXP3(+)，通过研究CD25(-)或CD45RA群体，可以确定这些调节性T细胞是重新产生的，而不是需要天然存在的调节性T细胞（Tregs）的扩增。因此，除了通过直接抑制环氧化酶介导的作用外，阿司匹林因其对免疫调节的更广泛影响，特别是其在治疗浓度下在人体中诱导耐受性DC的能力，仍然备受关注。
