Thomas E. Starzl Transplantation Institute, Pittsburgh, USA.
Curr Opin Organ Transplant. 2008 Aug;13(4):350-7. doi: 10.1097/MOT.0b013e328306116c.
Dendritic cells are well known for their potent ability, when fully differentiated or 'mature', to stimulate immune responses to antigens they present efficiently to T cells. Mature DC have been used as experimental cellular vaccines against cancer, an approach that has produced limited immune responses and tumor regressions in patients with late-stage disease. Contrastingly, with respect to therapy of organ transplant rejection, we highlight herein how immature/maturation-resistant dendritic cells are emerging as 'negative cellular vaccines', with the ability to induce anergy/apoptosis in alloreactive T cells, while potentially stimulating regulatory T-cell populations.
New insights have shed increasing light on dendritic cell immunobiology and the complex processes by which dendritic cell subsets perform both stimulatory and tolerogenic functions. Alloantigen-pulsed host-derived dendritic cells, conditioned with immunosuppressive agents (e.g. rapamycin (RAPA) or dexamethasone) or anti-inflammatory cytokines (e.g. IL-10), are resistance to maturation, and when infused systemically, can promote experimental transplant tolerance, especially when combined with low-dose immunosuppression. Such 'negative' dendritic cell cellular vaccines are proving effective at stimulating/enriching for alloantigen-specific regulatory T cell.
Increased understanding of what makes dendritic cells tolerogenic, accompanied by the identification of agents that stably inhibit dendritic cell maturation in the face of proinflammatory stimuli, has given rise to several promising experimental tolerance-inducing protocols. Their translation into clinical testing has the potential to reduce patients' reliance on indefinite, drug-based immunosuppression.
树突状细胞以其强大的能力而闻名，当它们完全分化或“成熟”时，能够有效地将它们呈现的抗原刺激免疫反应，从而刺激 T 细胞。成熟的树突状细胞已被用作针对癌症的实验性细胞疫苗，这种方法在晚期疾病患者中仅产生了有限的免疫反应和肿瘤消退。相比之下，就器官移植排斥反应的治疗而言，我们在此强调，不成熟/抗成熟的树突状细胞如何作为“阴性细胞疫苗”出现，具有诱导同种反应性 T 细胞失能/凋亡的能力，同时可能刺激调节性 T 细胞群体。
对树突状细胞免疫生物学的新见解以及树突状细胞亚群发挥刺激和耐受功能的复杂过程，越来越多地揭示出来。用免疫抑制药物（如雷帕霉素（RAPA）或地塞米松）或抗炎细胞因子（如 IL-10）处理的同种抗原脉冲宿主来源的树突状细胞对成熟具有抗性，并且当全身输注时，可以促进实验性移植耐受，特别是与低剂量免疫抑制相结合时。这种“阴性”树突状细胞细胞疫苗在刺激/富集同种抗原特异性调节性 T 细胞方面已被证明是有效的。
对使树突状细胞具有耐受性的因素的理解的增加，伴随着鉴定在面对促炎刺激时稳定抑制树突状细胞成熟的试剂，已经产生了几种有前途的实验性诱导耐受方案。将它们转化为临床测试有可能减少患者对无限期、基于药物的免疫抑制的依赖。
