Lee W C, Qiani S, Wan Y, Li W, Xing Z, Gauldie J, Fung J J, Thomson A W, Lu L
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Immunology. 2000 Oct;101(2):233-41. doi: 10.1046/j.1365-2567.2000.00096.x.
Mouse bone marrow-derived myeloid dendritic cells (DC) propagated in granulocyte-macrophage colony-stimulating factor and transforming growth factor-beta1 (TGF-beta1) (so-called 'TGF-beta DC') are phenotypically immature, and prolong allograft survival. Interleukin-10 (IL-10) has been shown to inhibit the maturation of DC by down-regulating surface major histocompatibility complex (MHC) class II, co-stimulatory and adhesion molecule expression. Genetic engineering of TGF-beta DC to overexpress IL-10 might enhance their tolerogenic potential. In this study, adenoviral (Ad) vectors encoding the mouse IL-10 gene were transduced into B10 (H2b) TGF-beta DC. Transduction with Ad-IL-10 at a multiplicity of infection (MOI) of 50-100 resulted in a modest reduction in the incidence of DC expressing surface MHC class II, CD40, CD80 and CD86. Paradoxically, Ad-IL-10 transduction enhanced the allostimulatory activity of DC in mixed leucocyte reactions and cytotoxic T lymphocyte assays, and increased their natural killer cell stimulatory activity. Systemic injection of normal C3H recipients with Ad-IL-10-transduced B10-DC 7 days before organ transplantation, exacerbated heart graft rejection and augmented circulating anti-donor alloantibody titres. Contrasting effects were observed in relation to tumour growth. All mice preimmunized with Ad-IL-10-transduced, tumour antigen (B16F10)-pulsed DC developed palpable tumours, associated with significant inhibition of splenic anti-tumour cytotoxic T lymphocyte generation. Animals pretreated with control Ad-LacZ-transduced, B16F10-pulsed DC however, remained tumour free. These findings are consistent with the multifunctional immunomodulatory properties of mammalian IL-10.
在粒细胞-巨噬细胞集落刺激因子和转化生长因子-β1（TGF-β1）（所谓的“TGF-β树突状细胞”）中增殖的小鼠骨髓来源的髓样树突状细胞（DC）在表型上不成熟，并能延长同种异体移植物的存活时间。白细胞介素-10（IL-10）已被证明可通过下调表面主要组织相容性复合体（MHC）II类、共刺激分子和黏附分子的表达来抑制DC的成熟。对TGF-β树突状细胞进行基因工程改造以使其过表达IL-10可能会增强其致耐受性潜能。在本研究中，将编码小鼠IL-10基因的腺病毒（Ad）载体转导至B10（H2b）TGF-β树突状细胞中。以50-100的感染复数（MOI）用Ad-IL-10进行转导，导致表达表面MHC II类、CD40、CD80和CD86的DC发生率适度降低。矛盾的是，Ad-IL-10转导增强了DC在混合淋巴细胞反应和细胞毒性T淋巴细胞试验中的同种异体刺激活性，并增加了它们的自然杀伤细胞刺激活性。在器官移植前7天，给正常C3H受体全身注射Ad-IL-10转导的B10-DC，会加剧心脏移植物排斥反应并提高循环抗供体同种异体抗体滴度。在肿瘤生长方面观察到了相反的效果。所有用Ad-IL-10转导、肿瘤抗原（B16F10）脉冲处理的树突状细胞进行预免疫的小鼠都出现了可触及的肿瘤，这与脾抗肿瘤细胞毒性T淋巴细胞生成的显著抑制有关。然而，用对照Ad-LacZ转导、B16F10脉冲处理的树突状细胞预处理的动物仍然没有肿瘤。这些发现与哺乳动物IL-10的多功能免疫调节特性一致。
