摘要
目的全反式维甲酸(At-RA)是维生素A的代谢产物,它具有抑制炎症、调节免疫和诱导细胞分化等作用。而炎症和免疫因素是器官移植排斥反应的主要致病原因。因此,本研究在小鼠异位心脏移植模型上探讨At-RA对器官移植排斥反应的作用。
方法本研究以C57BL/6小鼠为受体,BALB/c或C3H/He小鼠为供体建立了小鼠腹腔心脏移植模型。在急性排斥反应模型,从心脏移植前1天开始受体小鼠每天经口给予At-RA (3 mg·kg-1)或玉米油0.2ml,观察移植物存活时间。移植术后第7天,摘取供心行组织病理学、免疫组化和western blot检查。并摘取受体小鼠脾脏,分别用混合淋巴细胞反应、western blot和流式细胞术进行细胞增殖反应、细胞因子和免疫细胞的检测。在慢性排斥反应模型,对照组小鼠术后第1,3,5天腹腔注射CD154单克隆抗体MR1(10mg·kg-1),实验组小鼠在对照组的基础上从移植前1天开始每天经口给予At-RA (3mg·kg-1),连续给予60天,观察移植物存活时间。移植术后第100天,摘取供心行组织病理学、免疫组化和PCR检查。然后我们从经At-RA干预的移植物长期存活的受体小鼠分离CDllc+树突状细胞(DC),并将其过继转移到刚接受心脏移植的受体小鼠体内,观察移植物存活时间。移植术后第7天,收集受体小鼠的脾细胞,用流式细胞术进行免疫细胞的检测。
结果在急性排斥反应模型,At-RA组的移植物存活时间比对照组显著延长(95.17±12.40天vs.9.67±0.62天,P<0.05),移植物排斥反应分级评分显著降低。与对照组相比,At-RA组受体小鼠的脾细胞对供体(BALB/c)脾细胞的增殖反应较低,但对第三方(C3H/He)来源的脾细胞的增殖反应无差别。At-RA组受体小鼠的脾脏CD4+CD25+Foxp3+调节T细胞(Treg)的比例显著高于对照组,而CD4+IL-17+ Th17细胞的比例显著低于对照组。At-RA组心脏移植物Foxp3的表达显著高于对照组。At-RA组受体小鼠的脾脏和心脏移植物TGF-β蛋白的表达显著高于对照组,而IL-6蛋白的表达显著低于对照组。At-RA组受体小鼠的脾脏CDllc+ DC表面CD40、CD80、CD86和MHCⅡ的表达较对照组显著降低。在慢性移植模型,At-RA组移植物的管腔阻塞率、内膜与中膜面积之比、移植物纤维化区域、CD4和CD8阳性细胞浸润以及IFN-γ和IL-10 mRNA表达较对照组均明显降低。CDllc+ DC过继转移显著延长了BALB/c来源的供心的存活时间,而没有延长C3H／He来源的供心的存活时间。并且CDllc+ DC过继转移小鼠的脾细胞的Treg细胞比例较对照组升高,但Th17细胞的比例降低。
结论At-RA通过直接的和DC介导的对Treg和Th17细胞的调节作用延长了心脏移植物的存活时间,减轻了心脏移植物血管病变。本研究为临床应用At-RA治疗心脏移植物排斥反应提供了理论基础和实验依据。
Background. All-trans retinoic acid (At-RA) has been shown to have a variety of functions including roles in inhibiting inflammation and modulating immune function, as well as inducing cell differentiation. Since inflammatory and immunological factors appear to be major pathological elements of allograft rejection, we speculated that At-RA may offer therapeutic promise. Here, we investigated the role of At-RA in allograft rejection in a murine cardiac transplantation model.
Methods. We performed fully MHC-mismatched heterotopic murine cardiac transplantation. In acute rejection, recipient mice were given At-RA (3 mg·kg-1·d-1) or vehicle orally beginning 1 day before cardiac transplantation. Seven days after transplantation, allografts were harvested for histological, immunohistochemical and western blot examination. In addition, recipient spleens were studied by mixed lymphocyte reaction, western blot and flow cytometry. In chronic rejection, recipient mice were given anti-CD 154 antibody MR1 (10mg·kg-1) intraperitoneally on days 1,3 and 5 or anti-CD 154 antibody MR1 (10mg·kg-1) on days 1,3 and 5 plus At-RA (3 mg·kg-1·d-1) beginning day-1 for 60 consective days. Allografts were harvested for histological, immunohistochemical and PCR study 100 days after transplantation. Then we transfered CD11c+ dendritic cells (DC) from At-RA-treated long-term graft accepting hosts into mice that recently underwent transplantation. Recipient spleens were harvested for flow cytometry analysis at 7 days after transplantation.
Results. In acute rejection, animals given At-RA showed significantly longer cardiac allograft survival than control mice (95.17±12.40 days versus 9.67±0.62 days, P＜0.05). Splenocytes isolated from At-RA-treated mice elicited a significantly lower proliferation in response to donor (BALB/c) but not third-party (C3H/He) splenocytes than controls. In vivo At-RA treatment increased frequency of splenic CD4+CD25+ Foxp3+ regulatory T cells (Treg) and reduced frequency of splenic CD4+IL-17+Th17 cells. Moreover, At-RA treatment increased the expression of Foxp3 in allografts. Interestingly, At-RA increased the expression of TGF-βand prevented the expression of IL-6 in spleens and allografts. At-RA induced low expression of CD40, CD80, CD86, and MHCⅡmolecules of CD 11 c+ DC in vivo. In chronic rejection, neointimal hyperplasia was significantly lower in allografts from mice treated with MR1 plus At-RA (luminal occlusion,26.99±6.54%) than in those from control mice (47.27±5.27%, P<0.05). Allografts from MR1 plus At-RA-treated recipients showed significantly reduced expression of IFN-y and IL-10. Furthermore, transfer of CD11c+ DC from At-RA-treated long-term graft accepting hosts into mice that recently underwent transplantation resulted in donor (BALB/c)-specific graft acceptance and in a significantly higher frequency of splenic Treg and a significantly lower frequency of splenic Th17 cells.
Conclusions. At-RA prolongs allograft survival through direct and DC-mediated effects on Treg and Thl7 cells. Our data indicate that At-RA may have therapeutic properties ideally served for the treatment of allograft rejection.
引文
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