骨化三醇对原位肝移植后急性排斥反应的预防作用及机理研究
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摘要
近年来,随着外科技术、器官保存方法和免疫抑制剂的临床应用等领域的进步,肝移植受体的生存期已明显延长。然而,细胞介导的移植物急性排斥反应仍是器官移植后长期存活的主要障碍之一。据统计,肝移植后的急性排斥反应发生率约为40%～70%,并终将导致部分受体移植肝功能丧失。目前临床移植后治疗急性排斥反应主要依赖于非特异性的免疫抑制剂治疗,这些免疫抑制剂几乎完全抑制人体的免疫系统,显著增加病人罹患感染和肿瘤的危险性。因此,开发新型的免疫抑制剂,防止移植物排异反应一直是器官移植领域的研究热点。
骨化三醇是维生素D的活性形式,是调节钙磷代谢重要的内源性激素。近年来的研究证实骨化三醇具有广泛的免疫调节作用。多种免疫活性细胞如胸腺细胞、骨髓前髓细胞、外周血单个核细胞、巨噬细胞及活化的T细胞等细胞核内存在维生素D受体(VDR)。骨化三醇与VDR的结合,可以影响转录因子的活性,导致目的基因转录的激活或抑制。研究证实,骨化三醇可以直接抑制Th1细胞分泌IL-2、IFN-γ和TNF-α等Th1类细胞因子,并可以直接刺激Th2细胞分泌IL-4,IL-5和IL-10等Th2类细胞因子。同时骨化三醇可以抑制B淋巴细胞分泌IL-12,进一步抑制T淋巴细胞的分化和活化。对抗原递呈细胞,体外研究证实骨化三醇可以明显抑制树突状细胞(DC)表达MHCII类分子及B7.1、B7.2分子和CD40等表面标志,影响共刺激信号的传导。同时,其他研究证实骨化三醇可以直接抑制细胞毒性T淋巴细胞(CTL)和自然杀伤细胞(NK)介导的细胞毒性。新近的多个研究尚证实骨化三醇可以诱导致耐受型DC利调节性T细胞(Treg)的产生,从而调节免疫反应。
浙江大学博士学位论文
骨化二醇在体内的免疫调几}y作用近年亦得到少’‘泛的研究。一些研究认为骨化二醇可以
延长多种非血管化或血管化器官如皮肤、心脏和肾脏等移植后移植物的生存期,并可以避
免传统的免疫抑制治疗后常见的感染、骨质疏松等副作用。但亦有一些研究认为骨化二醇
并不能明显延长移植物存活期。因而J骨化二醇在器官移植后排斥反应中的作用不能定论。
移植宿主启动急性排斥反应实施对移植物的损伤是一个非常复杂的过程,由各种免疫
活性细胞和多种蛋白质共同参与完成,T细胞的增殖、活化是其中心环一竹。在同种移植中,
静!卜的T淋巴细胞识别抗原递呈细胞(APC)递呈的抗原后活化,在共刺激因子的协同作
用下,合成、分泌白细胞介素2(IL一2)和自细胞介素2受体(!L一ZR),推动丁淋巴细胞由
GO期进入Gl期,开始增殖。T淋巴细胞增殖后进一步分化为细胞毒性T淋巴细胞(C下L)
和辅助性下细胞(Th)。CTL通过穿孔素和颗粒酶B途径或Fas IFasL途径,导致靶细胞
表面发生致死信号,并通过细胞浆内Caspase蛋白家族和Bd一2蛋白家族的传导,进一步
将细胞表面信号传导至细胞核内,使细胞核内染色体发生断裂,细胞凋亡,最终导致移植
物失功。T卜细胞则通过分泌相应的细胞因子,使体内细胞因子网络向启动急性排斥反应的
Thl型或向诱导免疫耐受的ThZ型发生偏移,实现对移植后免疫反应的调节。
骨化三醇对原位肝移植后急性排斥反应的调节作用尚未得到深入的研究。肝脏作为一
个免疫特惠器官,在移植后表现其独特的免疫反应特点。预防性应用骨化二醇对原位肝移
植后的免疫反应的调节作用具有什么动态特征?凋亡途径是否参与了碑骨化三醇对移植物的
保护作用?骨化三醇与经典的免疫抑制剂是否具有正协同作用?本研究针对以上问题展
开,探讨骨化三醇对原位肝移植后急性排斥反应的调节作用和机理。
材料与方法
第一部分研究观察骨化二醇对大鼠原位肝移植后急性排斥反应的调节作用。建立大鼠
原位肝移植模型,实验分4组进行:!织.为Wistar*晰star同基因移植组(Syn grouP);
一l至日.为SD、Wjstar急性排斥组(Rej grouP);l!I组SD、WIStar CsA处理织一(CSA group),
原位肝移植后应用环抱霉素A(CsA)3.omg.kg一1.d一,腹腔内注射,移植后。一13大用药;Iv
组SD、晰 star谓,化二醇处理爹R(Caleitriol group):原位肝移植后应用骨,化二醇(Calcitriol)
1.opg.kg一,.d一1腹腔内注射,移植后。一13大用药。各组分别于移植后1、3、5、7、12、3od
浙江大学博士学位论文
各处死3例受体采集标本,并每组留取6例受体观察移植后一般情况和存活时间。测定移
植后各个时点移植物功能和受体外周血Ca十十浓度;观察移植物急性排斥反应病理学特征;
采用单向混合淋巴细胞反应检测移植后受体脾脏单个核细胞对异体抗原刺激的反应能力;
采用流式细胞技术分析移植后受体外周血CO4、COS细胞的含量并计算CO4lCOS比例;
采用EUSA方法测定移植后受体外周血IL一2,4,10和IFN一Y等细胞因子浓度;采用蛋白印
迹(W白stem以。tting)方法检测移植物局部细胞因子蛋白表达量;采用免疫组织化学方法
检测移植物局部CO4、COS及CO25阳性细胞浸润程度。
第止部分研究观察骨化二醇对移植后肝脏细胞凋亡的影响。利用第一部分采集的标本,
采用下UNEL技术和透射电镜技术观察移植物细胞形态学特征,采用免疫组织化学方法或
蛋白印迹方法检测移植物局部凋亡相关蛋白Caspase一3,Bax,Bcl一 xL,Bcl一2等的表达。
第二部分研究观察骨化二醇和CsA联用是否具有正协同作用。利用
IntroductionRecently, with the progress in the surgical technique, preservation method of the graft and the clinical application of immunosuppressive agent, survivals of recipients after liver transplantation have been improved significantly. However, the acute rejection which is mediated by cell immune is still the main obstacle which influences the result of transplantation. It was reported that the morbidity of acute rejection is about 40%~70%, and it will result in a part of grafts lose their function. The main clinical means at present to inhibit acute rejection is nonspecial immunosuppressant therapy. Those immunosuppressants can inhibit the function of immunol system entirely. It will increase the risk of suffering from infection and tumor. So, it always was focused in the transplantation domain to explore a new immunosuppressant which can inhibit acute rejection of allograft.Calcitriol is the active metabolite of the vitamin D. It is an endogenesis hormone that is the key regulator of calcium calcium, phosphorus, and bone metabolism. Pevious study has demonstrated that calcitriol has comprehensive immunoregulation effect. It has been demonstrated that the VDR appear in a wide variety of immunoactive cell such as
thymocyte, promyelocyte and mononuclear cell, macrophage, activated T lymphocyte in peripheral blood. Vitamin D functions as immunoactive agent through combining with VDR. Combination of calcitriol with VDR influences the activity of transcripition factor. As a consequence, transcription of target gene was inhibited or activated. The in vitro studies have demonstrated that calcitriol can inhibit directly the Th1-type T cell to secret cytokine such as IL-2, IFN-γ and TNF-a, and stimulate Th2-type T cell to secret cytokine such as IL-4, -5 and IL-10. Meanwhile, calcitriol can inhibit the secretion of IL-12 by B lymphocyte, resulting in the further regulation of T cell proliferation and activation. Other studies have suggested that calcitriol may interfere with antigen-presenting cell function by decreasing MHC class II expression and B7.1, B7.2 and CD40 molecular expression resulting in the inhibition of co-stimmulator pathway. Finally, calcitriol has been shown to inhibit both the generation of cytotoxic T lymphocytes and natural killer NK-mediated cytotoxicity in vitro. Recently, capacity of calcitriol in induction of tolerogenic dendritic cells and regulatory T cells has been documented.The immunoregulation effect of calcitriol in vivo has been investigated. Several studuies have demonstrated that calcitriol can prolong the graft survival whether to non-vacularized graft such as skin, or to vacularized graft such as cardiac and kidney, and would not result in the side-effect such as infection and bone lose which was frequent in the process of classical immunosuppressant treatment. However, some documents also have reported that calcitriol did not prolong survival of murine skin grafts. Thus, it seemed unclear whether calcitriol played any role in the rejection of allograft. The process of injuring to graft which is initiated by host immune system is complex. It is participated by several kinds of immunoactive cells and small molecular proteins. The proliferation and activation is the key step of this procedure. In allografting, the rest T cell is activated by the stimulator from alloantigen which is presented by Antigen Presenting Cell (APC). With co-opration of the co-stimulate signal, T cell synthesizes and secretes IL-2 and expresses IL-2 R a. Combinition of IL-2 and IL-2 Ra impels T cells into the stage
of DNA synthesize, which will result in proliferation of T cell. The activated T cell subsequently differentiates into cytotoxic T lymphocyte (CTL) or T helper cell (Th). CTL can injury directly the target cell through perforin and granuenzyme B pathway and Fas/FasL pathway. With conduction of capase family and Bcl-2 family proteins in cytoplasm, the death signal from cell membranes is transmitted into nuclear. Chromosome is broken and apoptosis of target cell occur, which lead to dysfunction of gr
骨化三醇是维生素D的活性形式,是调节钙磷代谢重要的内源性激素。近年来的研究证实骨化三醇具有广泛的免疫调节作用。多种免疫活性细胞如胸腺细胞、骨髓前髓细胞、外周血单个核细胞、巨噬细胞及活化的T细胞等细胞核内存在维生素D受体(VDR)。骨化三醇与VDR的结合,可以影响转录因子的活性,导致目的基因转录的激活或抑制。研究证实,骨化三醇可以直接抑制Th1细胞分泌IL-2、IFN-γ和TNF-α等Th1类细胞因子,并可以直接刺激Th2细胞分泌IL-4,IL-5和IL-10等Th2类细胞因子。同时骨化三醇可以抑制B淋巴细胞分泌IL-12,进一步抑制T淋巴细胞的分化和活化。对抗原递呈细胞,体外研究证实骨化三醇可以明显抑制树突状细胞(DC)表达MHCII类分子及B7.1、B7.2分子和CD40等表面标志,影响共刺激信号的传导。同时,其他研究证实骨化三醇可以直接抑制细胞毒性T淋巴细胞(CTL)和自然杀伤细胞(NK)介导的细胞毒性。新近的多个研究尚证实骨化三醇可以诱导致耐受型DC利调节性T细胞(Treg)的产生,从而调节免疫反应。
浙江大学博士学位论文
骨化二醇在体内的免疫调几}y作用近年亦得到少’‘泛的研究。一些研究认为骨化二醇可以
延长多种非血管化或血管化器官如皮肤、心脏和肾脏等移植后移植物的生存期,并可以避
免传统的免疫抑制治疗后常见的感染、骨质疏松等副作用。但亦有一些研究认为骨化二醇
并不能明显延长移植物存活期。因而J骨化二醇在器官移植后排斥反应中的作用不能定论。
移植宿主启动急性排斥反应实施对移植物的损伤是一个非常复杂的过程,由各种免疫
活性细胞和多种蛋白质共同参与完成,T细胞的增殖、活化是其中心环一竹。在同种移植中,
静!卜的T淋巴细胞识别抗原递呈细胞(APC)递呈的抗原后活化,在共刺激因子的协同作
用下,合成、分泌白细胞介素2(IL一2)和自细胞介素2受体(!L一ZR),推动丁淋巴细胞由
GO期进入Gl期,开始增殖。T淋巴细胞增殖后进一步分化为细胞毒性T淋巴细胞(C下L)
和辅助性下细胞(Th)。CTL通过穿孔素和颗粒酶B途径或Fas IFasL途径,导致靶细胞
表面发生致死信号,并通过细胞浆内Caspase蛋白家族和Bd一2蛋白家族的传导,进一步
将细胞表面信号传导至细胞核内,使细胞核内染色体发生断裂,细胞凋亡,最终导致移植
物失功。T卜细胞则通过分泌相应的细胞因子,使体内细胞因子网络向启动急性排斥反应的
Thl型或向诱导免疫耐受的ThZ型发生偏移,实现对移植后免疫反应的调节。
骨化三醇对原位肝移植后急性排斥反应的调节作用尚未得到深入的研究。肝脏作为一
个免疫特惠器官,在移植后表现其独特的免疫反应特点。预防性应用骨化二醇对原位肝移
植后的免疫反应的调节作用具有什么动态特征?凋亡途径是否参与了碑骨化三醇对移植物的
保护作用?骨化三醇与经典的免疫抑制剂是否具有正协同作用?本研究针对以上问题展
开,探讨骨化三醇对原位肝移植后急性排斥反应的调节作用和机理。
材料与方法
第一部分研究观察骨化二醇对大鼠原位肝移植后急性排斥反应的调节作用。建立大鼠
原位肝移植模型,实验分4组进行:!织.为Wistar*晰star同基因移植组(Syn grouP);
一l至日.为SD、Wjstar急性排斥组(Rej grouP);l!I组SD、WIStar CsA处理织一(CSA group),
原位肝移植后应用环抱霉素A(CsA)3.omg.kg一1.d一,腹腔内注射,移植后。一13大用药;Iv
组SD、晰 star谓,化二醇处理爹R(Caleitriol group):原位肝移植后应用骨,化二醇(Calcitriol)
1.opg.kg一,.d一1腹腔内注射,移植后。一13大用药。各组分别于移植后1、3、5、7、12、3od
浙江大学博士学位论文
各处死3例受体采集标本,并每组留取6例受体观察移植后一般情况和存活时间。测定移
植后各个时点移植物功能和受体外周血Ca十十浓度;观察移植物急性排斥反应病理学特征;
采用单向混合淋巴细胞反应检测移植后受体脾脏单个核细胞对异体抗原刺激的反应能力;
采用流式细胞技术分析移植后受体外周血CO4、COS细胞的含量并计算CO4lCOS比例;
采用EUSA方法测定移植后受体外周血IL一2,4,10和IFN一Y等细胞因子浓度;采用蛋白印
迹(W白stem以。tting)方法检测移植物局部细胞因子蛋白表达量;采用免疫组织化学方法
检测移植物局部CO4、COS及CO25阳性细胞浸润程度。
第止部分研究观察骨化二醇对移植后肝脏细胞凋亡的影响。利用第一部分采集的标本,
采用下UNEL技术和透射电镜技术观察移植物细胞形态学特征,采用免疫组织化学方法或
蛋白印迹方法检测移植物局部凋亡相关蛋白Caspase一3,Bax,Bcl一 xL,Bcl一2等的表达。
第二部分研究观察骨化二醇和CsA联用是否具有正协同作用。利用
IntroductionRecently, with the progress in the surgical technique, preservation method of the graft and the clinical application of immunosuppressive agent, survivals of recipients after liver transplantation have been improved significantly. However, the acute rejection which is mediated by cell immune is still the main obstacle which influences the result of transplantation. It was reported that the morbidity of acute rejection is about 40%~70%, and it will result in a part of grafts lose their function. The main clinical means at present to inhibit acute rejection is nonspecial immunosuppressant therapy. Those immunosuppressants can inhibit the function of immunol system entirely. It will increase the risk of suffering from infection and tumor. So, it always was focused in the transplantation domain to explore a new immunosuppressant which can inhibit acute rejection of allograft.Calcitriol is the active metabolite of the vitamin D. It is an endogenesis hormone that is the key regulator of calcium calcium, phosphorus, and bone metabolism. Pevious study has demonstrated that calcitriol has comprehensive immunoregulation effect. It has been demonstrated that the VDR appear in a wide variety of immunoactive cell such as
thymocyte, promyelocyte and mononuclear cell, macrophage, activated T lymphocyte in peripheral blood. Vitamin D functions as immunoactive agent through combining with VDR. Combination of calcitriol with VDR influences the activity of transcripition factor. As a consequence, transcription of target gene was inhibited or activated. The in vitro studies have demonstrated that calcitriol can inhibit directly the Th1-type T cell to secret cytokine such as IL-2, IFN-γ and TNF-a, and stimulate Th2-type T cell to secret cytokine such as IL-4, -5 and IL-10. Meanwhile, calcitriol can inhibit the secretion of IL-12 by B lymphocyte, resulting in the further regulation of T cell proliferation and activation. Other studies have suggested that calcitriol may interfere with antigen-presenting cell function by decreasing MHC class II expression and B7.1, B7.2 and CD40 molecular expression resulting in the inhibition of co-stimmulator pathway. Finally, calcitriol has been shown to inhibit both the generation of cytotoxic T lymphocytes and natural killer NK-mediated cytotoxicity in vitro. Recently, capacity of calcitriol in induction of tolerogenic dendritic cells and regulatory T cells has been documented.The immunoregulation effect of calcitriol in vivo has been investigated. Several studuies have demonstrated that calcitriol can prolong the graft survival whether to non-vacularized graft such as skin, or to vacularized graft such as cardiac and kidney, and would not result in the side-effect such as infection and bone lose which was frequent in the process of classical immunosuppressant treatment. However, some documents also have reported that calcitriol did not prolong survival of murine skin grafts. Thus, it seemed unclear whether calcitriol played any role in the rejection of allograft. The process of injuring to graft which is initiated by host immune system is complex. It is participated by several kinds of immunoactive cells and small molecular proteins. The proliferation and activation is the key step of this procedure. In allografting, the rest T cell is activated by the stimulator from alloantigen which is presented by Antigen Presenting Cell (APC). With co-opration of the co-stimulate signal, T cell synthesizes and secretes IL-2 and expresses IL-2 R a. Combinition of IL-2 and IL-2 Ra impels T cells into the stage
of DNA synthesize, which will result in proliferation of T cell. The activated T cell subsequently differentiates into cytotoxic T lymphocyte (CTL) or T helper cell (Th). CTL can injury directly the target cell through perforin and granuenzyme B pathway and Fas/FasL pathway. With conduction of capase family and Bcl-2 family proteins in cytoplasm, the death signal from cell membranes is transmitted into nuclear. Chromosome is broken and apoptosis of target cell occur, which lead to dysfunction of gr
引文
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2. Adorini L, Penna G, Giarratana N, et al. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004;89-90(1-5):437-41
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6. Alroy I, Towers TL, Freedman LP, et al. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol. 1995;15(10):5789-99
7. Barrat FJ, Cua DJ, Boonstra A,et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med. 2002; 195(5):603-16.
8. Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167(9):4974-80.
9. D'Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101(1):252-62.
10. Xu H, Soruri A, Gieseler RK, et al. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-ll antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol. 1993;38(6):535-40.
11. Griffin MD, Lutz WH, Phan VA, et al. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun. 2000;270(3):701-8
12. Griffin MD, Lutz W, Phan VA, et al. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A. 2001,98(12):6800-5.
13. Merino F, Alvarez-Mon M, DeLa Hena A, et al. Regulation of natural killer cytotoxicity by 1,25-dihydroxyvitamin D3. Cell Immunol 1989; 118(2): 328-36.
14. Meehan MA, Kennan RH, Lemire JM. 1, 25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 1992; 149(2): 400-9.
15. Adorini L, Giarratana N, Penna G Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol. 2004; 16(2): 127-34.
16. Mathieu C, Waer M, Laureys J, et al. Activated form of vitamin D [1,25(OH)2D3] and its analogs are dose-reducing agents for cyclosporine in vitro and in vivo. Transplant Proc. 1994;26(5):3048-9.
17. Hullett DA, Cantorna MT, Redaelli C, et al. Prolongation of allograft survival by 1,25-dihydroxyvitamin D3. Transplantation. 1998;66(7):824-8.
18. Veyron P, Pamphile R, Binderup L, et al. Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin aliograft survival in mice. Transpl Immunol. 1993;1(1):72-6.
19. Redaelli CA, Wagner M, Gunter-Duwe D, et al. 1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. Kidney Int. 2002;61(1):288-96
20. Jordan SC, Nigata M, Mullen Y. 1,25-Dihydroxyvitamin D3 prolongs allograft rat cardiac allograft survival. In: Norman AW, Schaefer K, Grigoleit H-G, v. Herrath D, eds. Molecular, cellular and clinical endocrinology. Berlin: Walter de Gruyter, 1988: 334.
21. Lemire JM, Archer DC, Khulkorni A, et al. Prolongation of the survival of murine cardiac allografts by the vitamin D3 analogue 1,25-dihydroxzy-L16-cholecalciferol. Transplantation 1991; 54: 762-3.
22. Kemnitz J, Ringe B, Cohnert TR, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection. Hum Pathol. 1989; 20(2): 132-43.
23. An international panel. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology, 1997, 25:658-63.
24. Cantorna MT, Hayes Cl, DeLuca HF. 1, 25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis: a model of multiple sclerosis. Proc Natl Acad Sci USA 1996; 93: 7861-4
25. Hayes CE. Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc. 2000; 59(4):531-5.
26. Mathieu C, Waer M, Casteels K, et al. Prevention of type 1 diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3 KH1060. Endocrinology. 1995; 136: 866-72.
27. Foumier C, Gepner P, Sodouk M, et al. In vivo beneficial effects of cyclosporin and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin Immunol Immunopathol 1990; 54: 53-63.
28. Lemire JM, Ince A, Takoshima M. 1,25-Dihydroxyvitamin D3 attenuates the expression of murine lupus of MRL/1 mice. Autoimmunity 1992; 12:143-8.
29. Johnson C, Tufveson G MC1288-a vitamin D analogue with immunosuppressive effects on heart and small bowel grafts. Transpl Int, 1994, 7:392-7
30. Sharland A, Shastry S, Wang C, et al. Kinetics of intragraft cytokine expression, cellular infiltration, and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model: early activation and apoptosis is associated with liver graft acceptance. Transplantation. 1998;65(10):1370-7
31. Jiang S, Herrera O, Lechler Rl. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr Opin Immunol. 2004;16(5):550-7
32. Canning MO, Grotenhuis K, de Wit H, et al. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol. 2001;145(3):351-7.
33. Miyanari N, Yamaguchi Y, Matsuno K, et al. Persistent infiltration of CD45RC- CD4+ T cells, Th2-like effector cells, in prolonging hepatic allografts in rats pretreated with a donor-specific blood transfusion. Hepatology. 1997;25(4):1008-13.
34. Sharland A, Yan Y, Wang C, et al. Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance. Transplantation. 1999;68(11):1736-45
35. Gibelli NE, Pinho-Apezzato ML, Miyatani HT, et al. Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study. Transplant Proc. 2004;36(4):956-7
36. Oliveira G, Xavier P, Murphy B, et al. Cytokine analysis of human renal allograft aspiration biopsy cultures supernatants predicts acute rejection. Nephroi Dial Transplant. 1998; 13(2):417-22
37. Baan CC, Niesters HG, Metselaar HJ, et al. Increased intragraft IL-15 mRNA expression after liver transplantation. Clin Transplant. 1998; 12(3): 212-8
38. Hidalgo LG, Halloran PF. et al. Role of IFN-gamma in allograft rejection. Crit Rev Immunol. 2002;22(4):317-49
39. Affleck DG, Bull DA, Albanil A, et al. lnterleukin-18 production following murine cardiac transplantation: correlation with histologic rejection and the induction of INF-gamma. J Interferon Cytokine Res. 2001; 21(1): 1-9.
40. Warle MC, Farhan A, Metselaar HJ, et al. In vitro cytokine production of TNFalpha and IL-13 correlates with acute liver transplant rejection. Hum Immunol. 2001 ;62(11): 1258-65.
41. Pawelec G, Rehbein A, Schlotz E, et al. Cytokine modulation of TH1/TH2 phenotype differentiation in directly alloresponsive CD4+ human T cells. Transplantation. 1996;62(8):1095-101
42. Saggi BH, Fisher RA, Bu D, et al. Intragraft cytokine expression and tolerance induction in rat renal allografts. Transplantation. 1999; 67(2): 206-10.
43. He XY, Chen J, Verma N, et al. Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses. Transplantation. 1998 May 15; 65(9): 1145-52.
44. Jiang H, Liu C, Xu J, et al. Gene transfer of interleukin-4 delays acute rejection of splenic allografts in rats. Transplant Proc. 2004 ;36(5): 1600-3.
45. De Fazio SR, Gozzo JJ. Role of graft interleukin-10 expression in the tolerogenicity of neonatal skin allografts. Transplantation. 2000;70(9):1371-7.
46. Tashiro H, Shinozaki K, Yahata H, et al. Prolongation of liver allograft survival after interleukin-10 gene transduction 24-48 hours before donation, Transplantation, 2000,70:336-9.
47. Fairchild PJ, Waldmann H. Dendritic cells and prospects for transplantation tolerance. Curr Opin Immunol. 2000; 12(5): 528-35.
48. Tan L, Howell WM, Smith JL, et al. Sequential monitoring of peripheral T-lymphocyte cytokine gene expression in the early post renal allograft period. Transplantation. 2001 ;71(6):751-9.
49. David A, Chetritt J, Guillot C, et al. Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats. Gene Then 2000;7(6):505-10
50. Tashiro H, Shinozaki K, Yahata H, et al. Prolongation of liver allograft survival after interleukin-10 gene transduction 24-48 hours before donation, Transplantation, 2000,70:336-9.
51. Brandt C, Yang J, Schmitt-Knosalla I, et al. Allo-specific T-cells encoding for viral IL-10 exert strong immunomodulatory effects in vitro but fail to prevent graft rejection. Am J Transplant. 2005;5(2):268-81.
52. Buonocore S, Van Meirvenne S, Demoor FX, et al. Dendritic cells transduced with viral interieukin 10 or Fas ligand: no evidence for induction of allotolerance in vivo. Transplantation. 2002 ;73 (1 Suppl):S27-30.
2. Adorini L, Penna G, Giarratana N, et al. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004;89-90(1-5):437-41
3. Lemire J. 1, 25-Dihydroxyvitamin D3-a hormone with immunomodulatory properties. Z Rheumatol. 2000;59 Suppl 1:24-7.
4. Bettoun DJ, Lu J, Khalifa B, et al. Ligand modulates VDR-Ser/Thr protein phosphatase interaction and p70S6 kinase phosphorylation in a cell-context-dependent manner. J Steroid Biochem Mol Biol. 2004;89-90(1-5):195-8
5. Takeuchi A, Reddy GS, Kobayashi T, et al. Nuclear factor of activated T cells (NFAT) as a molecular target for 1 alpha,25-dihydroxyvitamin D3-mediated effects. J Immunol. 1998;160(1):209-18
6. Alroy I, Towers TL, Freedman LP, et al. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol. 1995;15(10):5789-99
7. Barrat FJ, Cua DJ, Boonstra A,et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med. 2002; 195(5):603-16.
8. Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167(9):4974-80.
9. D'Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998;101(1):252-62.
10. Xu H, Soruri A, Gieseler RK, et al. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-ll antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol. 1993;38(6):535-40.
11. Griffin MD, Lutz WH, Phan VA, et al. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun. 2000;270(3):701-8
12. Griffin MD, Lutz W, Phan VA, et al. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A. 2001,98(12):6800-5.
13. Merino F, Alvarez-Mon M, DeLa Hena A, et al. Regulation of natural killer cytotoxicity by 1,25-dihydroxyvitamin D3. Cell Immunol 1989; 118(2): 328-36.
14. Meehan MA, Kennan RH, Lemire JM. 1, 25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 1992; 149(2): 400-9.
15. Adorini L, Giarratana N, Penna G Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol. 2004; 16(2): 127-34.
16. Mathieu C, Waer M, Laureys J, et al. Activated form of vitamin D [1,25(OH)2D3] and its analogs are dose-reducing agents for cyclosporine in vitro and in vivo. Transplant Proc. 1994;26(5):3048-9.
17. Hullett DA, Cantorna MT, Redaelli C, et al. Prolongation of allograft survival by 1,25-dihydroxyvitamin D3. Transplantation. 1998;66(7):824-8.
18. Veyron P, Pamphile R, Binderup L, et al. Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin aliograft survival in mice. Transpl Immunol. 1993;1(1):72-6.
19. Redaelli CA, Wagner M, Gunter-Duwe D, et al. 1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. Kidney Int. 2002;61(1):288-96
20. Jordan SC, Nigata M, Mullen Y. 1,25-Dihydroxyvitamin D3 prolongs allograft rat cardiac allograft survival. In: Norman AW, Schaefer K, Grigoleit H-G, v. Herrath D, eds. Molecular, cellular and clinical endocrinology. Berlin: Walter de Gruyter, 1988: 334.
21. Lemire JM, Archer DC, Khulkorni A, et al. Prolongation of the survival of murine cardiac allografts by the vitamin D3 analogue 1,25-dihydroxzy-L16-cholecalciferol. Transplantation 1991; 54: 762-3.
22. Kemnitz J, Ringe B, Cohnert TR, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection. Hum Pathol. 1989; 20(2): 132-43.
23. An international panel. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology, 1997, 25:658-63.
24. Cantorna MT, Hayes Cl, DeLuca HF. 1, 25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis: a model of multiple sclerosis. Proc Natl Acad Sci USA 1996; 93: 7861-4
25. Hayes CE. Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc. 2000; 59(4):531-5.
26. Mathieu C, Waer M, Casteels K, et al. Prevention of type 1 diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3 KH1060. Endocrinology. 1995; 136: 866-72.
27. Foumier C, Gepner P, Sodouk M, et al. In vivo beneficial effects of cyclosporin and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin Immunol Immunopathol 1990; 54: 53-63.
28. Lemire JM, Ince A, Takoshima M. 1,25-Dihydroxyvitamin D3 attenuates the expression of murine lupus of MRL/1 mice. Autoimmunity 1992; 12:143-8.
29. Johnson C, Tufveson G MC1288-a vitamin D analogue with immunosuppressive effects on heart and small bowel grafts. Transpl Int, 1994, 7:392-7
30. Sharland A, Shastry S, Wang C, et al. Kinetics of intragraft cytokine expression, cellular infiltration, and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model: early activation and apoptosis is associated with liver graft acceptance. Transplantation. 1998;65(10):1370-7
31. Jiang S, Herrera O, Lechler Rl. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr Opin Immunol. 2004;16(5):550-7
32. Canning MO, Grotenhuis K, de Wit H, et al. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol. 2001;145(3):351-7.
33. Miyanari N, Yamaguchi Y, Matsuno K, et al. Persistent infiltration of CD45RC- CD4+ T cells, Th2-like effector cells, in prolonging hepatic allografts in rats pretreated with a donor-specific blood transfusion. Hepatology. 1997;25(4):1008-13.
34. Sharland A, Yan Y, Wang C, et al. Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance. Transplantation. 1999;68(11):1736-45
35. Gibelli NE, Pinho-Apezzato ML, Miyatani HT, et al. Basiliximab-chimeric anti-IL2-R monoclonal antibody in pediatric liver transplantation: comparative study. Transplant Proc. 2004;36(4):956-7
36. Oliveira G, Xavier P, Murphy B, et al. Cytokine analysis of human renal allograft aspiration biopsy cultures supernatants predicts acute rejection. Nephroi Dial Transplant. 1998; 13(2):417-22
37. Baan CC, Niesters HG, Metselaar HJ, et al. Increased intragraft IL-15 mRNA expression after liver transplantation. Clin Transplant. 1998; 12(3): 212-8
38. Hidalgo LG, Halloran PF. et al. Role of IFN-gamma in allograft rejection. Crit Rev Immunol. 2002;22(4):317-49
39. Affleck DG, Bull DA, Albanil A, et al. lnterleukin-18 production following murine cardiac transplantation: correlation with histologic rejection and the induction of INF-gamma. J Interferon Cytokine Res. 2001; 21(1): 1-9.
40. Warle MC, Farhan A, Metselaar HJ, et al. In vitro cytokine production of TNFalpha and IL-13 correlates with acute liver transplant rejection. Hum Immunol. 2001 ;62(11): 1258-65.
41. Pawelec G, Rehbein A, Schlotz E, et al. Cytokine modulation of TH1/TH2 phenotype differentiation in directly alloresponsive CD4+ human T cells. Transplantation. 1996;62(8):1095-101
42. Saggi BH, Fisher RA, Bu D, et al. Intragraft cytokine expression and tolerance induction in rat renal allografts. Transplantation. 1999; 67(2): 206-10.
43. He XY, Chen J, Verma N, et al. Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses. Transplantation. 1998 May 15; 65(9): 1145-52.
44. Jiang H, Liu C, Xu J, et al. Gene transfer of interleukin-4 delays acute rejection of splenic allografts in rats. Transplant Proc. 2004 ;36(5): 1600-3.
45. De Fazio SR, Gozzo JJ. Role of graft interleukin-10 expression in the tolerogenicity of neonatal skin allografts. Transplantation. 2000;70(9):1371-7.
46. Tashiro H, Shinozaki K, Yahata H, et al. Prolongation of liver allograft survival after interleukin-10 gene transduction 24-48 hours before donation, Transplantation, 2000,70:336-9.
47. Fairchild PJ, Waldmann H. Dendritic cells and prospects for transplantation tolerance. Curr Opin Immunol. 2000; 12(5): 528-35.
48. Tan L, Howell WM, Smith JL, et al. Sequential monitoring of peripheral T-lymphocyte cytokine gene expression in the early post renal allograft period. Transplantation. 2001 ;71(6):751-9.
49. David A, Chetritt J, Guillot C, et al. Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats. Gene Then 2000;7(6):505-10
50. Tashiro H, Shinozaki K, Yahata H, et al. Prolongation of liver allograft survival after interleukin-10 gene transduction 24-48 hours before donation, Transplantation, 2000,70:336-9.
51. Brandt C, Yang J, Schmitt-Knosalla I, et al. Allo-specific T-cells encoding for viral IL-10 exert strong immunomodulatory effects in vitro but fail to prevent graft rejection. Am J Transplant. 2005;5(2):268-81.
52. Buonocore S, Van Meirvenne S, Demoor FX, et al. Dendritic cells transduced with viral interieukin 10 or Fas ligand: no evidence for induction of allotolerance in vivo. Transplantation. 2002 ;73 (1 Suppl):S27-30.