Th细胞及其细胞因子在预测大鼠肝移植免疫状态中的价值研究
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摘要
临床器官移植的长期存活率得到明显提高,已成为终末期器官功能衰竭病人的最佳治疗方案。然而,同种异体排斥反应仍然是器官移植的主要障碍。诱导机体抗原特异性免疫耐受,是解决器官移植排斥的根本方法。
目前,尚无系统的免疫学和免疫遗传学的对移植耐受预测和判断的方法,临床上采用组织活检鉴别移植物的免疫状态虽然准确,但相对机体的免疫状态的变化有明显的滞后性,并且标本的获得严重受限。在器官移植术后常规运用大剂量的免疫抑制剂治疗方案,带来了严重的副作用,如肾毒性、肝毒性、骨髓抑制等各器官系统的直接损害;病人免疫力降低会导致的各种感染和恶性肿瘤发病率上升等严重的后果。所以,如何建立预测器官移植受体免疫耐受的方法,为临床移植病人用药个体化提供依据,对耐受病人用药减量或停药及时给以指导,改善病人预后和生活质量,减轻经济负担,对免疫排斥的早期诊断及病人的预后作出判断,这对自发耐受发生率较高的肝脏移植的意义尤为重要。
1986年,mosmann等发现CD4+T辅助细胞可产生Th1型(IL-2、IFN-γ)利Th2型(IL-4、IL-10)细胞因子。最近有研究表明,Th1和Th2型细胞因子表达的变化和免疫耐受的产生和维持以及排斥反应的发生具有非常密切的关系。
此课题应用短期小剂量CsA诱导大鼠同种异体肝移植达到长期接受和耐受的移植模型,拟在研究Th细胞在外周血的表达和移植肝脏中的表达是否存在相似性,能否作为肝移植术后急性排斥和耐受的预测指标。
浙江人学博」:学位论文
材料和方法
实验为同种异体移植:I组为BN斗BN大鼠同基因对照组(Syn group);工工组为Lewis oBN
CSA处理组(CsA group),大鼠肝移植后用环抱霉素A(CsA)2.omg/kg/d皮下注射0一7天;IH
组为Lewis分BN人鼠急性排斥组(Rej group)。移植后1、3、5、7、14天切取移植肝脏用于
病理学、移植肝脏中基因产物的逆转录聚合酶链式反应和原位杂交反应检测;受体脾用于淋
巴细胞亚群激光共聚焦显微镜检测;受体外周血用于淋巴细胞亚群的流式细胞检测、血清细
胞因子EL工SA的检测。另外设亚组观察移植后一般情况和肝移植术后受体的存活时间。
结果
1.各组大鼠术后一般状态及生存时间
同基因组,均长期存活,(大于100天);CsA处理组大鼠,6只中4只获得长期存活,
用药期间一般状态差,停药后好转;排斥组大鼠术后28一38天全部死亡,中位存活时间33.3
天。同基因组和CsA处理组术后一般状态明显好于排斥组。
2.病理表现及移植排斥反应病理分级
同基因组移植大鼠各个时间段病理学检测均未发现明显排斥。CsA处理组第l大未见
有排斥表现,第3天可见淋巴细胞浸润,平均排斥分级分别为0.48,第5、7天淋巴细胞细
胞浸润更加明显,平均排斥分级分别为0.67和l.ro,14大淋巴细胞浸润,胆管增生存在,
平均排斥分级为1.16。排斥组术后第l大汇管区少量炎性细胞浸润,术后第3天汇管区淋
巴细胞细胞浸润明显,可见肝实质变性,平均排斥分级为1.59级,术后第5天中度排斥表
现,平均排斥分级为2.34级,术后第7天和14天,出现严重急性排斥表现,静脉内皮炎
明显,大量炎性细胞浸润,可见肝的变性坏死,胆管内皮炎或小胆管消失,平均排斥分级
分别为2.87不[一2.93。
除第1天外,CsA处理组各时间段的排斥分级明显高于同基因组(p<0.05或<0 .01):
而排斥组排斥分级和同基因组及CsA处理组相比升高更加明显(p<0 .05或<0 .01)。CsA处
理组不11排斥组内排斥分级比较p<0.001。
3.流式细胞仪检测外周血.CD4‘CD45RC细胞结果
浙江人学博l:学位论文
3.1 CD4+CD45RC.细胞在外周血单核细胞百分比中的变化
csA处理组从第3天开始升高,第14大达到高峰,高于同基因组,和同基因组相比有明
显差别(p<0 .001),第100天回到了手术第1大的水平。排斥组从第3天逐步升高,高于同
基因组和CsA处理组,与之相比差别有显著性(p刁.047、0.034),第5、7、14大分别和同
基因组和CsA处理组相比差异更明显(p<0.001)。
3.2 CD4‘CD45RC细胞在外周血单核细胞一百分比中的变化
CD4‘CD45RC细胞在外周血单核细胞中的一百分比在同基因组只有术后第3天有轻度的升高,
第5、7、14、100大接近术后第1大的水平。排斥组从第3天升高,然后逐步轻度下降。CsA
处理组从第5大突然升高,高于其他组,和同基因组和排斥组组相比有明显的差别(p=0 .018、
0.025);第7天达到高峰,和同基因组和排斥组组相比有明显差别(p=、<0 .001);第14天
较第7天有所下降,但是和同基因组和排斥组组相比仍较高,有明显的差别(p<0 .001);第
100大进一步下降,仍高于同基因组,但无显著性差别。
4.激光共聚焦显微镜检测CD4‘CD45RC细胞在脾淋巴细胞中的表达
每个高倍视野脾细胞中CD4CD45RC细胞数量变化:在同基因组的术后第1、3、5、7、14
的表达在4一6士1个;在CsA处理组第1、3、5、7、14大的表达分别为4士1、6士1、7土1、9
士2、9士l个;在排斥组第l、3、5、7、14大的表达分别为6士l、9士2、12士2、16士3、13
士2个。
5.Thl细胞因子在基因水平和外周血.中的表达
5.1工FN一丫在移植肝组织内mRNA水平和外周血.中的表达
IFN一Y在移植肝组织内mRNA水平和外周血.中的表达有极大相似性,同基因组在各时段均
未有表达。CsA处理组在1、3、5
IntroductionSignificant enhancement in long-term livability of clinic organ transplantation makes it an optimal therapy protocol for treatment of end stage disease. However, allogeneic rejection is still a major problem in organ transplantation. Inducing immunotolerance may be the essential method to overcome rejection reaction in organ transplantation.At present, there is no systemic predictability and estimation method for transplantation tolerance from the point of immunology and immunogenetics. Although clinically used biopsy provide accuracy results, but it display a significant hysteresis for immune state changes of organism. Meanwhile, there is a limitation in obtaining specimen. Conventional adopted large dosage immunosuppression therapy procedure post organ transplantation lead to serious side effects, such as direct damage to organ systems of kidney toxicity, liver toxicity and marrow suppression et al., various infection and morbidity increase of malignancy et al. resulted from decreased immunity of patients. Consequently, developing expectation method for accepter immune tolerance of organ transplantation to provide basis for clinically personal administration of transplantation patients, reducing or stopping administration for tolerance patients, improving patient prognosis and live quality, decreasing financial burden, early diagnosis to immunorejection and guiding prognosis
judgment of patient, this have significant influences on liver transplantations that have higher probability for spontaneous tolerance occurrence.In 1986, Mosmann et al. reported that CD4+ T cell can produce Th1 type (IL-2、 IFN-γ) and Th2 type (IL-4, IL-10) cytokines. Recent studies suggest that changes expressed by Thl and Th2 type cytokines are closely related with the appearance and maintaining of immunotolerance and occurrence of rejection reaction.Inducing allogeneic rejection transplantation liver of rat, to obtain long-term accepted and tolerance transplantation model, was achieved by administration of minimal dose CsA in our laboratory. The aim is to study whether there is similarity between expression of Th cell in peripheral blood and transplantation liver, whether it can be used as an estimation parameter for acute rejection and tolerance post liver transplantation.Materials and MethodsOrthotopic rat liver transplantation was performed. (Brown-Norway) BN rats were used as syngeneic donors and Lewis (LEW) were used as allogeneic donors. All recipients were BN rats who were randomly divided as follows: Group I: Syngeneic control (BN-to- BN); Group II: Acute rejection treated with CsA 2mg/kg/d by subcutaneous injection from day 0-7. Group III: Acute rejection (LEW -to- BN).A11 groups were subdivided into day 1, 3, 5, 7,14(n=4 each) posttransplantation respectively for sample harvesting; and additional subgroups (n=6) for observation of general situation and survival time. Liver graft specimens were harvested at indicated time to determine morphological changes by pathological examination and gene expression by reverse transcription-polymerase chain reaction (RT-PCR), as well as the hybridization in situ. Recipient splenocytes were isolated and phenotypes of spleen T cell subsets were analyzed by confocal microscopy. Recipient T cell subsets in peripheral blood were analyzed by flow cytometry and blood serum cytokines were analyzed by Enzyme-linked immunoadsordent assay (ELISA) .
Results1. The general situation and survival time posttransplantationThe general situation of syngeneic group was very well and survival time was over 100 days after transplantation. As for CsA treated group, the general situation was bad during CsA medication but with only mild rejection and the four of six recipients survived over 100 days .in the acute rejection group, all recipients died from 28 to38 days after transplantation and the mean survival time was 33.3 days. The general situation of syngeneic group and CsA treated group was remarkably better than that of acute rejection group.2. Histopathologic examination and rejection gradeNo signs
目前,尚无系统的免疫学和免疫遗传学的对移植耐受预测和判断的方法,临床上采用组织活检鉴别移植物的免疫状态虽然准确,但相对机体的免疫状态的变化有明显的滞后性,并且标本的获得严重受限。在器官移植术后常规运用大剂量的免疫抑制剂治疗方案,带来了严重的副作用,如肾毒性、肝毒性、骨髓抑制等各器官系统的直接损害;病人免疫力降低会导致的各种感染和恶性肿瘤发病率上升等严重的后果。所以,如何建立预测器官移植受体免疫耐受的方法,为临床移植病人用药个体化提供依据,对耐受病人用药减量或停药及时给以指导,改善病人预后和生活质量,减轻经济负担,对免疫排斥的早期诊断及病人的预后作出判断,这对自发耐受发生率较高的肝脏移植的意义尤为重要。
1986年,mosmann等发现CD4+T辅助细胞可产生Th1型(IL-2、IFN-γ)利Th2型(IL-4、IL-10)细胞因子。最近有研究表明,Th1和Th2型细胞因子表达的变化和免疫耐受的产生和维持以及排斥反应的发生具有非常密切的关系。
此课题应用短期小剂量CsA诱导大鼠同种异体肝移植达到长期接受和耐受的移植模型,拟在研究Th细胞在外周血的表达和移植肝脏中的表达是否存在相似性,能否作为肝移植术后急性排斥和耐受的预测指标。
浙江人学博」:学位论文
材料和方法
实验为同种异体移植:I组为BN斗BN大鼠同基因对照组(Syn group);工工组为Lewis oBN
CSA处理组(CsA group),大鼠肝移植后用环抱霉素A(CsA)2.omg/kg/d皮下注射0一7天;IH
组为Lewis分BN人鼠急性排斥组(Rej group)。移植后1、3、5、7、14天切取移植肝脏用于
病理学、移植肝脏中基因产物的逆转录聚合酶链式反应和原位杂交反应检测;受体脾用于淋
巴细胞亚群激光共聚焦显微镜检测;受体外周血用于淋巴细胞亚群的流式细胞检测、血清细
胞因子EL工SA的检测。另外设亚组观察移植后一般情况和肝移植术后受体的存活时间。
结果
1.各组大鼠术后一般状态及生存时间
同基因组,均长期存活,(大于100天);CsA处理组大鼠,6只中4只获得长期存活,
用药期间一般状态差,停药后好转;排斥组大鼠术后28一38天全部死亡,中位存活时间33.3
天。同基因组和CsA处理组术后一般状态明显好于排斥组。
2.病理表现及移植排斥反应病理分级
同基因组移植大鼠各个时间段病理学检测均未发现明显排斥。CsA处理组第l大未见
有排斥表现,第3天可见淋巴细胞浸润,平均排斥分级分别为0.48,第5、7天淋巴细胞细
胞浸润更加明显,平均排斥分级分别为0.67和l.ro,14大淋巴细胞浸润,胆管增生存在,
平均排斥分级为1.16。排斥组术后第l大汇管区少量炎性细胞浸润,术后第3天汇管区淋
巴细胞细胞浸润明显,可见肝实质变性,平均排斥分级为1.59级,术后第5天中度排斥表
现,平均排斥分级为2.34级,术后第7天和14天,出现严重急性排斥表现,静脉内皮炎
明显,大量炎性细胞浸润,可见肝的变性坏死,胆管内皮炎或小胆管消失,平均排斥分级
分别为2.87不[一2.93。
除第1天外,CsA处理组各时间段的排斥分级明显高于同基因组(p<0.05或<0 .01):
而排斥组排斥分级和同基因组及CsA处理组相比升高更加明显(p<0 .05或<0 .01)。CsA处
理组不11排斥组内排斥分级比较p<0.001。
3.流式细胞仪检测外周血.CD4‘CD45RC细胞结果
浙江人学博l:学位论文
3.1 CD4+CD45RC.细胞在外周血单核细胞百分比中的变化
csA处理组从第3天开始升高,第14大达到高峰,高于同基因组,和同基因组相比有明
显差别(p<0 .001),第100天回到了手术第1大的水平。排斥组从第3天逐步升高,高于同
基因组和CsA处理组,与之相比差别有显著性(p刁.047、0.034),第5、7、14大分别和同
基因组和CsA处理组相比差异更明显(p<0.001)。
3.2 CD4‘CD45RC细胞在外周血单核细胞一百分比中的变化
CD4‘CD45RC细胞在外周血单核细胞中的一百分比在同基因组只有术后第3天有轻度的升高,
第5、7、14、100大接近术后第1大的水平。排斥组从第3天升高,然后逐步轻度下降。CsA
处理组从第5大突然升高,高于其他组,和同基因组和排斥组组相比有明显的差别(p=0 .018、
0.025);第7天达到高峰,和同基因组和排斥组组相比有明显差别(p=、<0 .001);第14天
较第7天有所下降,但是和同基因组和排斥组组相比仍较高,有明显的差别(p<0 .001);第
100大进一步下降,仍高于同基因组,但无显著性差别。
4.激光共聚焦显微镜检测CD4‘CD45RC细胞在脾淋巴细胞中的表达
每个高倍视野脾细胞中CD4CD45RC细胞数量变化:在同基因组的术后第1、3、5、7、14
的表达在4一6士1个;在CsA处理组第1、3、5、7、14大的表达分别为4士1、6士1、7土1、9
士2、9士l个;在排斥组第l、3、5、7、14大的表达分别为6士l、9士2、12士2、16士3、13
士2个。
5.Thl细胞因子在基因水平和外周血.中的表达
5.1工FN一丫在移植肝组织内mRNA水平和外周血.中的表达
IFN一Y在移植肝组织内mRNA水平和外周血.中的表达有极大相似性,同基因组在各时段均
未有表达。CsA处理组在1、3、5
IntroductionSignificant enhancement in long-term livability of clinic organ transplantation makes it an optimal therapy protocol for treatment of end stage disease. However, allogeneic rejection is still a major problem in organ transplantation. Inducing immunotolerance may be the essential method to overcome rejection reaction in organ transplantation.At present, there is no systemic predictability and estimation method for transplantation tolerance from the point of immunology and immunogenetics. Although clinically used biopsy provide accuracy results, but it display a significant hysteresis for immune state changes of organism. Meanwhile, there is a limitation in obtaining specimen. Conventional adopted large dosage immunosuppression therapy procedure post organ transplantation lead to serious side effects, such as direct damage to organ systems of kidney toxicity, liver toxicity and marrow suppression et al., various infection and morbidity increase of malignancy et al. resulted from decreased immunity of patients. Consequently, developing expectation method for accepter immune tolerance of organ transplantation to provide basis for clinically personal administration of transplantation patients, reducing or stopping administration for tolerance patients, improving patient prognosis and live quality, decreasing financial burden, early diagnosis to immunorejection and guiding prognosis
judgment of patient, this have significant influences on liver transplantations that have higher probability for spontaneous tolerance occurrence.In 1986, Mosmann et al. reported that CD4+ T cell can produce Th1 type (IL-2、 IFN-γ) and Th2 type (IL-4, IL-10) cytokines. Recent studies suggest that changes expressed by Thl and Th2 type cytokines are closely related with the appearance and maintaining of immunotolerance and occurrence of rejection reaction.Inducing allogeneic rejection transplantation liver of rat, to obtain long-term accepted and tolerance transplantation model, was achieved by administration of minimal dose CsA in our laboratory. The aim is to study whether there is similarity between expression of Th cell in peripheral blood and transplantation liver, whether it can be used as an estimation parameter for acute rejection and tolerance post liver transplantation.Materials and MethodsOrthotopic rat liver transplantation was performed. (Brown-Norway) BN rats were used as syngeneic donors and Lewis (LEW) were used as allogeneic donors. All recipients were BN rats who were randomly divided as follows: Group I: Syngeneic control (BN-to- BN); Group II: Acute rejection treated with CsA 2mg/kg/d by subcutaneous injection from day 0-7. Group III: Acute rejection (LEW -to- BN).A11 groups were subdivided into day 1, 3, 5, 7,14(n=4 each) posttransplantation respectively for sample harvesting; and additional subgroups (n=6) for observation of general situation and survival time. Liver graft specimens were harvested at indicated time to determine morphological changes by pathological examination and gene expression by reverse transcription-polymerase chain reaction (RT-PCR), as well as the hybridization in situ. Recipient splenocytes were isolated and phenotypes of spleen T cell subsets were analyzed by confocal microscopy. Recipient T cell subsets in peripheral blood were analyzed by flow cytometry and blood serum cytokines were analyzed by Enzyme-linked immunoadsordent assay (ELISA) .
Results1. The general situation and survival time posttransplantationThe general situation of syngeneic group was very well and survival time was over 100 days after transplantation. As for CsA treated group, the general situation was bad during CsA medication but with only mild rejection and the four of six recipients survived over 100 days .in the acute rejection group, all recipients died from 28 to38 days after transplantation and the mean survival time was 33.3 days. The general situation of syngeneic group and CsA treated group was remarkably better than that of acute rejection group.2. Histopathologic examination and rejection gradeNo signs
引文
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13. Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation. 2002 May 15; 73(9): 1373-81.
14. Constant SL, Bottomly K. Induction of Thl and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997; 15:297-322.
15. GZ, von der Weid T, Lu B, et al. Interferon gamma signaling alters the function of T helper type 1 cells. J Exp Med. 2000 Oct 2;192(7):977-86.
16. Ohmori Y, Hamilton TA. IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages. J Immunol. 1997 Dec 1; 159(11): 5474-82.
17. Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999 Feb 19; 283(5405): 1183-6.
18. Yamamoto S, Okuda T, Yamasaki K, et al. FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation. Transplantation. 2004 Dec 15; 78(11): 1618-25.
19. Jiang H, Wynn C, Pan F, et al. Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production. Transplantation. 2002 Jun 15; 73(11): 1808-17.
20. Gassel HJ, Otto C, Gassel AM, et al. Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonalantibodies directed against CD25 and CD54 with subtherapeutic cyclosporine. Transplantation. 2000 Mar 27; 69(6): 1058-67.
21. Zimmermann FA, White DJ, Gokel JM, et al. Orthotopic liver transplantation in rats. Prolonging of survival time of allotransplants using cyclosporin A in an acute rejection model. Chir Forum Exp Klin Forsch. 1979;:339-44.
22. Huang WH, Yan Y, De Boer B, et al. A short course of cyclosporine immunosuppression inhibits rejection but not tolerance of rat liver allografts. Transplantation. 2003 Feb 15; 75(3): 368-74.
23. Hall BM, Jelbart ME, Gurley KE, et al. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med. 1985 Nov 1; 162(5): 1683-94.
24. Yamada K, Gianello PR, Ierino FL, et al. Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts. Transplantation. 1999 Feb 15; 67(3): 458-67.
25. Hutchinson IV, Bagnall W, Bryce P, et al. Differences in the mode of action of cyclosporine and FK 506.Transplant Proc. 1998 Jun; 30(4): 959-60.
26. Tocci MJ, Matkovich DA, Collier KA, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989 Jul 15; 143(2):718-26.
27. Smith KA. Interleukin-2: inception, impact, and implications. Science. 1988 May 27; 240(4856): 1169-76.
28. Krug A, Veeraswamy R, Pekosz A, et al. Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells.J Exp Med. 2003 Apr 7; 197(7): 899-906.
29. Khanna AK, Hosenpud JD.Cyclosporine induces the expression of the cyclin inhibitor p21. Transplantation. 1999 May 15;67(9): 1262-8.
30. Lee JI, Ganster R.W, Geller DA, et al. Cyclosporine A inhibits the expression of costimulatory molecules on in vitro-generated dendritic cells: association with reduced nuclear translocation of nuclear factor kappa B. Transplantation. 1999 Nov 15; 68(9): 1255-63.
31. Hylkema MN, van der Deen M, Pater JM, et al. Single expression of CD45RC and RT6 in correlation with T-helper 1 and T-helper 2 cytokine patterns in the rat. Cell Immunol. 2000 Feb 1; 199(2): 89-96.
32. Chung YH, Jun HS, Son M, et al. Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats. J Immunol. 2000 Sep 1; 165(5): 2866-76.
33. McCall MN, Shotton DM, Barclay AN. Expression of soluble isoforms of rat CD45. Analysis by electron microscopy and use in epitope mapping of anti-CD45R monoclonal antibodies. Immunology. 1992 Jun; 76(2): 310-7.
34. Yamaguchi Y, Miyanari N, Ichiguchi O, et al. Infiltrating CD45RC- T cells are associated with immunologic unresponsiveness induced by donor class I major histocompatibility complex antigens in rats. Hepatology. 1998 Aug; 28(2): 450-8.
35. 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 Apr; 25(4): 1008-13.
36. Chung SW, Yoshida EM, Cattral MS, et al. Donor-specific stimulation of peripheral blood mononuclear cells from recipients of orthotopic liver transplants is associated, in the absence of rejection, with type-2 cytokine production. Immunol Lett. 1998 Sep; 63(2): 91-6.
37. Gill RG, Coulombe M, Lafferty KJ. Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited. Immunol Rev. 1996 Feb; 149:75-96.
38. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10; 193(4257): 1007-8.
39. Rogers LA, Zlotnik A, Lee F, et al. . The maintenance of lytic specificity during the development of clones of cytotoxic T lymphocytes from single precursor cells. J Immunol Methods. 1991 Oct25; 143(2): 241-50.
40. Mocchegiani E, Malavolta M. NK and NKT cell functions in immunosenescence. Aging Cell. 2004 Aug; 3(4): 177-84.
41. Abou-Bacar A, Pfaff AW, Letscher-Bru V, et al. Role of gamma interferon and T cells in congenital Toxoplasma transmission. Parasite Immunol. 2004 Aug; 26(8-9): 315-8.
42. Wu S, Gessner R, von Stackelberg A, et al. Cytokine/cytokine receptor gene expression in childhood acute lymphoblastic leukemia. Cancer. 2005 Jan 13; 103(5): 1054-1063.
43. Curry H, Alvarez GR, Zwilling BS, et al. Toll-like Receptor 2 Stimulation Decreases IFN-gamma Receptor Expression in Mouse RAW264.7 Macrophages. J Interferon Cytokine Res. 2004 Dec; 24(12): 699-710.
44. Gill RG, Coulombe M, Lafferty KJ. Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited. Immunol Rev. 1996 Feb; 149:75-96.
45. Kamada N.The immunology of experimental liver transplantation in the rat. Immunology. 1985 Jul; 55(3): 369-89.
46. Thai NL, Fu F, Qian S, et al. Cytokine mRNA profiles in mouse orthotopic liver transplantation. Graft rejection is associated with augmented TH1 function. Transplantation. 1995 Jan 27; 59(2): 274-81.
47. Oliveira G, Xavier P, Murphy B, et al. Cytokine analysis of human renal allograft aspiration biopsy cultures supematants predicts acute rejection. Nephrol Dial Transplant. 1998 Feb; 13(2): 417-22.
48. Baan CC, Niesters HG, Metselaar HJ, et al. Increased intragraft IL-15 mRNA expression after liver transplantation. Clin Transplant. 1998 Jun; 12(3): 212-8.
49. Affleck DG, Bull DA, Albanil A, et al. Interleukin-18 production following murine cardiac transplantation: correlation with histologic rejection and the induction of INF-gamma. J Interferon Cytokine Res. 2001 Jan; 21(1): 1-9.
50. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell.IV.TH2 clones secrete a factor that inhibits cytokine production by TH1 clones. J ExpMed, 1989,170:2081-95
51. Furukawa Y, Becker G, Stinn JL, et al. Interleukin-10 augments allograft arterial disease: paradoxical effects of IL-10 in viv. Am J Pathol, 1999,155:1929-39.
52. Mottram PL, Han WR, Purcell LJ, et al. Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-gama in long-surviving mouse heart allograft after brief CD4-monoclonal antibody therapy. Transplantation, 1995,59:559-66.
53. Reiner SL, Wang ZE, Hatam F, et al. TH1 and TH2 cell antigen receptors in experimental leishmaniasis. Science. 1993 Mar 5; 259(5100): 1457-60.
54. Mosmann TR, Sad S.The expanding universe of T-cell subsets: Thl, Th2 and more. Immunol Today. 1996 Mar; 17(3): 138-46.
55. Fairchild PJ, Waldmann H. Dendritic cells and prospects for transplantation tolerance. Curr Opin Immunol. 2000 Oct; 12(5): 528-35.
56. David A, Chetritt J, Guillot, et al. Interleukin-10 producted by recombinant adenovirus prolongs survival of cardiac allografts in rats. Gnen Ther, 2000,7:505-10.
57. 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
58. Macneil IA, Suda T, Moore KW, et al. IL-10, a novel growth cofactor for mature and immature T cells. J Immunol. 1990 Dec 15; 145(12): 4167-73.
59. Zheng LM, Ojcius DM, Garaud F, et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med. 1996 Aug 1; 184(2): 579-84.
60. Jiang H, Wynn C, Pan F, et al. Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production. Transplantation. 2002 Jun 15; 73(11): 1808-17.
61. Ke B, Ritter T, Kato H, et al. Regulatory cells potentiate the efficacy of IL-4 gene transfer by up-regulating Th2-dependent expression of protective molecules in the infectious tolerance pathway in transplant recipients. J Immunol. 2000 Jun 1; 164(11): 5739-45.
62. Saggi BH, Fisher RA, Bu D, et al. Intragraft cytokine expression and tolerance induction in rat renal allografts. Transplantation. 1999 Jan 27; 67(2): 206-10.
63. 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.
64. Debonera F, Aldeguer X, Shen X, et al. Activation of interleukin-6/STAT3 and liver regeneration following transplantation. Activation of interleukin-6/STAT3 and liver regeneration following transplantation. J Surg Res. 2001 Apr; 96(2): 289-95.
65. Bartlett AS, McCall JL, Ameratunga R, et al. Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat. Liver Transpl. 2002 May;8(5): 458-68.
66. Miki C, McMaster P, Mayer AD, et al. Factors predicting perioperative cytokine response in patients undergoing liver transplantation. Crit Care Med. 2000 Feb; 28(2): 351 -4.
67. Boros P, Suehiro T, Curtiss S, et al. Differential contribution of graft and recipient to perioperative TNF-alpha, IL-1 beta, IL-6 and IL-8 levels and correlation with early graft function in clinical liver transplantation. Clin Transplant. 1997 Dec; 11(6): 588-92.
68. Slotwinski R, Olszewski WL, Paluszkiewicz R, et al. Serum cytokine concentration after liver lobe harvesting for transplantation. Ann Transplant. 2002; 7(3): 36-9.
69. Weiner HL.Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today. 1997 Jul; 18(7): 335-43.
70. Billiau AD, Sefrioui H, Overbergh L, et al. Transforming growth factor-beta inhibits lymphokine activated killer cytotoxicity of bone marrow cells: implications for the graft-versus-leukemia effect in irradiation allogeneic bone marrow chimeras. Transplantation. 2001 Jan 27; 71(2): 292-9.
71. Patil S, Wildey GM, Brown TL, et al. Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis. J Biol Chem. 2000 Dec 8; 275(49): 38363-70.
72. Boussiotis VA, Chen ZM, Zeller JC, et al. Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease. Blood. 2001 Jan 15; 97(2): 565-71.
73. Sankaran D, Asderakis A, Ashraf S, et al. Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int. 1999 Jul; 56(1): 281-8.
74. Hughes JR, Hughes VF, Trull AK, et al. Blood levels of TGFbetal in liver transplant recipients receiving either tacrolimus or micro-emulsified cyclosporine. Transplantation. 1999 Aug 27; 68(4): 583-6.
75. Wehrhan F, Rodel F, Grabenbauer GG, et al. Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing. Radiother Oncol. 2004 Sep; 72(3): 297-303.
76. Ben-Ari Z, Pappo O, Druzd T, et al. Role of cytokine gene polymorphism and hepatic transforming growth factor betal expression in recurrent hepatitis C after liver transplantation. Cytokine. 2004 Jul 7; 27(1): 7-14.
77. Schultze-Mosgau S, Wehrhan F, Rodel F, et al. Anti-TGFbetal antibody for modulation of expression of endogenous transforming growth factor beta 1 to prevent fibrosis after plastic surgery in rats. Br J Oral Maxillofac Surg. 2004 Apr; 42(2): 112-9.
2. Starzl TE,Kashiwagi N, Porter KA, et al.Studies of homograph sex and gamma globulin phenotypes after orthotopic homotransplantations of the human liver[J].Surg Forum, 1969, 20: 374-376.
3. Takatsuki M, Uemoto S,Inomata Y, et al. Weaning of immunosuppression in Living donor Liver transplant recipients [J]. Transplantation.2001.72(3); 449-54.
4. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1; 136(7): 2348-57.
5. Blois SM, Joachim R, Kandil J, et al. Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile. J Immunol. 2004 May 15; 172(10): 5893-9.
6. Athanassopoulos P, Vaessen LM, Maat AP, et al. Peripheral blood dendritic cells in human end-stage heart failure and the early post-transplant period: evidence for systemic Thl immune responses. Eur J Cardiothorac Surg. 2004 Apr; 25(4): 619-26.
7. Wang YL, Tang ZQ, Gao W, et al. Influence of Thl, Th2, and Th3 cytokines during the early phase after liver transplantation. Transplant Proc. 2003 Dec; 35(8): 3024-5.
8. Gassel HJ.OttoC, transplantation 2000;69:1058; Zimmermann FA,White DJ, Gokel JM, Chir forum Exp Klin Forch 1979:339.
9. Kemnitz J, Ringe B, Cohnert TR, et al. Bile duct injury as a part of diagnostic criteria for liver allograft rejection. Hum Pathol. 1989 Feb; 20(2): 132-43.
10. Maggi E, Biswas P, Del Prete G, et al. Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol. 1991 Feb 15; 146(4): 1169-74.
11. Romagnani S.Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug; 12(8): 256-7.
12. Krieger NR, Yin DP, Fathman CG. CD4+ but not CD8+ cells are essential for allorejection. J Exp Med. 1996 Nov 1; 184(5): 2013-8.
13. Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation. 2002 May 15; 73(9): 1373-81.
14. Constant SL, Bottomly K. Induction of Thl and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997; 15:297-322.
15. GZ, von der Weid T, Lu B, et al. Interferon gamma signaling alters the function of T helper type 1 cells. J Exp Med. 2000 Oct 2;192(7):977-86.
16. Ohmori Y, Hamilton TA. IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse macrophages. J Immunol. 1997 Dec 1; 159(11): 5474-82.
17. Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999 Feb 19; 283(5405): 1183-6.
18. Yamamoto S, Okuda T, Yamasaki K, et al. FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation. Transplantation. 2004 Dec 15; 78(11): 1618-25.
19. Jiang H, Wynn C, Pan F, et al. Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production. Transplantation. 2002 Jun 15; 73(11): 1808-17.
20. Gassel HJ, Otto C, Gassel AM, et al. Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonalantibodies directed against CD25 and CD54 with subtherapeutic cyclosporine. Transplantation. 2000 Mar 27; 69(6): 1058-67.
21. Zimmermann FA, White DJ, Gokel JM, et al. Orthotopic liver transplantation in rats. Prolonging of survival time of allotransplants using cyclosporin A in an acute rejection model. Chir Forum Exp Klin Forsch. 1979;:339-44.
22. Huang WH, Yan Y, De Boer B, et al. A short course of cyclosporine immunosuppression inhibits rejection but not tolerance of rat liver allografts. Transplantation. 2003 Feb 15; 75(3): 368-74.
23. Hall BM, Jelbart ME, Gurley KE, et al. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med. 1985 Nov 1; 162(5): 1683-94.
24. Yamada K, Gianello PR, Ierino FL, et al. Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts. Transplantation. 1999 Feb 15; 67(3): 458-67.
25. Hutchinson IV, Bagnall W, Bryce P, et al. Differences in the mode of action of cyclosporine and FK 506.Transplant Proc. 1998 Jun; 30(4): 959-60.
26. Tocci MJ, Matkovich DA, Collier KA, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989 Jul 15; 143(2):718-26.
27. Smith KA. Interleukin-2: inception, impact, and implications. Science. 1988 May 27; 240(4856): 1169-76.
28. Krug A, Veeraswamy R, Pekosz A, et al. Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells.J Exp Med. 2003 Apr 7; 197(7): 899-906.
29. Khanna AK, Hosenpud JD.Cyclosporine induces the expression of the cyclin inhibitor p21. Transplantation. 1999 May 15;67(9): 1262-8.
30. Lee JI, Ganster R.W, Geller DA, et al. Cyclosporine A inhibits the expression of costimulatory molecules on in vitro-generated dendritic cells: association with reduced nuclear translocation of nuclear factor kappa B. Transplantation. 1999 Nov 15; 68(9): 1255-63.
31. Hylkema MN, van der Deen M, Pater JM, et al. Single expression of CD45RC and RT6 in correlation with T-helper 1 and T-helper 2 cytokine patterns in the rat. Cell Immunol. 2000 Feb 1; 199(2): 89-96.
32. Chung YH, Jun HS, Son M, et al. Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats. J Immunol. 2000 Sep 1; 165(5): 2866-76.
33. McCall MN, Shotton DM, Barclay AN. Expression of soluble isoforms of rat CD45. Analysis by electron microscopy and use in epitope mapping of anti-CD45R monoclonal antibodies. Immunology. 1992 Jun; 76(2): 310-7.
34. Yamaguchi Y, Miyanari N, Ichiguchi O, et al. Infiltrating CD45RC- T cells are associated with immunologic unresponsiveness induced by donor class I major histocompatibility complex antigens in rats. Hepatology. 1998 Aug; 28(2): 450-8.
35. 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 Apr; 25(4): 1008-13.
36. Chung SW, Yoshida EM, Cattral MS, et al. Donor-specific stimulation of peripheral blood mononuclear cells from recipients of orthotopic liver transplants is associated, in the absence of rejection, with type-2 cytokine production. Immunol Lett. 1998 Sep; 63(2): 91-6.
37. Gill RG, Coulombe M, Lafferty KJ. Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited. Immunol Rev. 1996 Feb; 149:75-96.
38. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10; 193(4257): 1007-8.
39. Rogers LA, Zlotnik A, Lee F, et al. . The maintenance of lytic specificity during the development of clones of cytotoxic T lymphocytes from single precursor cells. J Immunol Methods. 1991 Oct25; 143(2): 241-50.
40. Mocchegiani E, Malavolta M. NK and NKT cell functions in immunosenescence. Aging Cell. 2004 Aug; 3(4): 177-84.
41. Abou-Bacar A, Pfaff AW, Letscher-Bru V, et al. Role of gamma interferon and T cells in congenital Toxoplasma transmission. Parasite Immunol. 2004 Aug; 26(8-9): 315-8.
42. Wu S, Gessner R, von Stackelberg A, et al. Cytokine/cytokine receptor gene expression in childhood acute lymphoblastic leukemia. Cancer. 2005 Jan 13; 103(5): 1054-1063.
43. Curry H, Alvarez GR, Zwilling BS, et al. Toll-like Receptor 2 Stimulation Decreases IFN-gamma Receptor Expression in Mouse RAW264.7 Macrophages. J Interferon Cytokine Res. 2004 Dec; 24(12): 699-710.
44. Gill RG, Coulombe M, Lafferty KJ. Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited. Immunol Rev. 1996 Feb; 149:75-96.
45. Kamada N.The immunology of experimental liver transplantation in the rat. Immunology. 1985 Jul; 55(3): 369-89.
46. Thai NL, Fu F, Qian S, et al. Cytokine mRNA profiles in mouse orthotopic liver transplantation. Graft rejection is associated with augmented TH1 function. Transplantation. 1995 Jan 27; 59(2): 274-81.
47. Oliveira G, Xavier P, Murphy B, et al. Cytokine analysis of human renal allograft aspiration biopsy cultures supematants predicts acute rejection. Nephrol Dial Transplant. 1998 Feb; 13(2): 417-22.
48. Baan CC, Niesters HG, Metselaar HJ, et al. Increased intragraft IL-15 mRNA expression after liver transplantation. Clin Transplant. 1998 Jun; 12(3): 212-8.
49. Affleck DG, Bull DA, Albanil A, et al. Interleukin-18 production following murine cardiac transplantation: correlation with histologic rejection and the induction of INF-gamma. J Interferon Cytokine Res. 2001 Jan; 21(1): 1-9.
50. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell.IV.TH2 clones secrete a factor that inhibits cytokine production by TH1 clones. J ExpMed, 1989,170:2081-95
51. Furukawa Y, Becker G, Stinn JL, et al. Interleukin-10 augments allograft arterial disease: paradoxical effects of IL-10 in viv. Am J Pathol, 1999,155:1929-39.
52. Mottram PL, Han WR, Purcell LJ, et al. Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-gama in long-surviving mouse heart allograft after brief CD4-monoclonal antibody therapy. Transplantation, 1995,59:559-66.
53. Reiner SL, Wang ZE, Hatam F, et al. TH1 and TH2 cell antigen receptors in experimental leishmaniasis. Science. 1993 Mar 5; 259(5100): 1457-60.
54. Mosmann TR, Sad S.The expanding universe of T-cell subsets: Thl, Th2 and more. Immunol Today. 1996 Mar; 17(3): 138-46.
55. Fairchild PJ, Waldmann H. Dendritic cells and prospects for transplantation tolerance. Curr Opin Immunol. 2000 Oct; 12(5): 528-35.
56. David A, Chetritt J, Guillot, et al. Interleukin-10 producted by recombinant adenovirus prolongs survival of cardiac allografts in rats. Gnen Ther, 2000,7:505-10.
57. 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
58. Macneil IA, Suda T, Moore KW, et al. IL-10, a novel growth cofactor for mature and immature T cells. J Immunol. 1990 Dec 15; 145(12): 4167-73.
59. Zheng LM, Ojcius DM, Garaud F, et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med. 1996 Aug 1; 184(2): 579-84.
60. Jiang H, Wynn C, Pan F, et al. Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production. Transplantation. 2002 Jun 15; 73(11): 1808-17.
61. Ke B, Ritter T, Kato H, et al. Regulatory cells potentiate the efficacy of IL-4 gene transfer by up-regulating Th2-dependent expression of protective molecules in the infectious tolerance pathway in transplant recipients. J Immunol. 2000 Jun 1; 164(11): 5739-45.
62. Saggi BH, Fisher RA, Bu D, et al. Intragraft cytokine expression and tolerance induction in rat renal allografts. Transplantation. 1999 Jan 27; 67(2): 206-10.
63. 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.
64. Debonera F, Aldeguer X, Shen X, et al. Activation of interleukin-6/STAT3 and liver regeneration following transplantation. Activation of interleukin-6/STAT3 and liver regeneration following transplantation. J Surg Res. 2001 Apr; 96(2): 289-95.
65. Bartlett AS, McCall JL, Ameratunga R, et al. Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat. Liver Transpl. 2002 May;8(5): 458-68.
66. Miki C, McMaster P, Mayer AD, et al. Factors predicting perioperative cytokine response in patients undergoing liver transplantation. Crit Care Med. 2000 Feb; 28(2): 351 -4.
67. Boros P, Suehiro T, Curtiss S, et al. Differential contribution of graft and recipient to perioperative TNF-alpha, IL-1 beta, IL-6 and IL-8 levels and correlation with early graft function in clinical liver transplantation. Clin Transplant. 1997 Dec; 11(6): 588-92.
68. Slotwinski R, Olszewski WL, Paluszkiewicz R, et al. Serum cytokine concentration after liver lobe harvesting for transplantation. Ann Transplant. 2002; 7(3): 36-9.
69. Weiner HL.Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today. 1997 Jul; 18(7): 335-43.
70. Billiau AD, Sefrioui H, Overbergh L, et al. Transforming growth factor-beta inhibits lymphokine activated killer cytotoxicity of bone marrow cells: implications for the graft-versus-leukemia effect in irradiation allogeneic bone marrow chimeras. Transplantation. 2001 Jan 27; 71(2): 292-9.
71. Patil S, Wildey GM, Brown TL, et al. Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis. J Biol Chem. 2000 Dec 8; 275(49): 38363-70.
72. Boussiotis VA, Chen ZM, Zeller JC, et al. Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease. Blood. 2001 Jan 15; 97(2): 565-71.
73. Sankaran D, Asderakis A, Ashraf S, et al. Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int. 1999 Jul; 56(1): 281-8.
74. Hughes JR, Hughes VF, Trull AK, et al. Blood levels of TGFbetal in liver transplant recipients receiving either tacrolimus or micro-emulsified cyclosporine. Transplantation. 1999 Aug 27; 68(4): 583-6.
75. Wehrhan F, Rodel F, Grabenbauer GG, et al. Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing. Radiother Oncol. 2004 Sep; 72(3): 297-303.
76. Ben-Ari Z, Pappo O, Druzd T, et al. Role of cytokine gene polymorphism and hepatic transforming growth factor betal expression in recurrent hepatitis C after liver transplantation. Cytokine. 2004 Jul 7; 27(1): 7-14.
77. Schultze-Mosgau S, Wehrhan F, Rodel F, et al. Anti-TGFbetal antibody for modulation of expression of endogenous transforming growth factor beta 1 to prevent fibrosis after plastic surgery in rats. Br J Oral Maxillofac Surg. 2004 Apr; 42(2): 112-9.