Stax Annelein M, Gelderman Kyra A, Schlagwein Nicole, Essers Maria C, Kamerling Sylvia W A, Woltman Andrea M, van Kooten Cees
Department Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Transplantation. 2008 Nov 15;86(9):1275-82. doi: 10.1097/TP.0b013e31818a6682.
Dendritic cells (DC) can exert powerful immune stimulatory as well as regulatory functions and are therefore important tools for therapeutic strategies. Dexamethasone (Dex) was previously shown to inhibit DC maturation and to induce regulatory properties both in vitro and in vivo. Here, we investigated the immunoregulatory role of DexDC in two different rat acute rejection models of kidney transplantation.
Rat DC were generated from BN and DA bone marrow in the presence of the corticosteroid, Dex. The function of Dex-modulated DC was analyzed in vitro and in vivo, using a BN to LEW and a DA to LEW renal transplantation model in the absence of other forms of immunosuppression. T cells of transplanted rats were isolated and restimulated with donor mature DC (lipopolysaccharide [LPS] or CD40L activated). T-cell responsiveness was analyzed by proliferative capacity and IFN-gamma production.
Stimulation of Dex-modulated rat DC with LPS resulted in normal IL-10 production, whereas synthesis of IL-12 was impaired. In accordance, the capacity of LPS-DexDC to stimulate T-cell activation was decreased. In both renal transplantation models, treatment with donor-derived LPS-DexDC induced a significant donor-specific T-cell hyporesponse. However, pretreatment did not result in a prolonged graft survival.
In two fully mismatched kidney transplantation models, donor-derived LPS-DexDC induce a donor-specific T-cell hyporesponse. However, in this setting allograft survival was not improved, suggesting an important role for T cells with indirect alloreactivity. Understanding the underlying mechanism involved in the rejection process will improve the development of a cell-based immunotherapy.
树突状细胞（DC）可发挥强大的免疫刺激及调节功能，因此是治疗策略的重要工具。先前研究表明，地塞米松（Dex）在体外和体内均可抑制DC成熟并诱导调节特性。在此，我们在两种不同的大鼠肾移植急性排斥模型中研究了DexDC的免疫调节作用。
在皮质类固醇Dex存在的情况下，从BN和DA骨髓中生成大鼠DC。在无其他形式免疫抑制的情况下，使用BN到LEW以及DA到LEW的肾移植模型，在体外和体内分析Dex调节的DC的功能。分离移植大鼠的T细胞，并用供体成熟DC（脂多糖[LPS]或CD40L激活）进行再刺激。通过增殖能力和IFN-γ产生分析T细胞反应性。
用LPS刺激Dex调节的大鼠DC可导致正常的IL-10产生，而IL-12的合成受损。相应地，LPS-DexDC刺激T细胞活化的能力降低。在两种肾移植模型中，用供体来源的LPS-DexDC治疗均诱导了显著的供体特异性T细胞低反应性。然而，预处理并未导致移植物存活时间延长。
在两种完全不匹配的肾移植模型中，供体来源的LPS-DexDC诱导了供体特异性T细胞低反应性。然而，在此情况下同种异体移植物存活并未改善，提示具有间接同种异体反应性的T细胞起重要作用。了解排斥过程中涉及的潜在机制将有助于改进基于细胞的免疫治疗的发展。
