Treg细胞诱导移植免疫耐受及其在皮肤移植中的作用机制研究
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摘要
器官移植是现今挽救终末期器官功能衰竭患者生命的最终有效途径。如何控制器官移植后排斥发应，诱发宿主对移植物的免疫耐受，一直是移植免疫领域研究的热点及难题。迄今，防治移植排斥的主要对策仍然是通过各种途径抑制宿主的免疫功能，但现在临床使用的各种免疫抑制剂都存在非特异性抑制的突出弱点。近年来提出的特异性免疫耐受理论为移植免疫的研究指明了方向：即通过诱导机体仅对移植物抗原产生耐受，而保留和不干预机体的其他免疫功能，达到既延长移植物存活时间，又使对宿主自身免疫功能的影响降到最低限度的效果。国内外在这方面做过的研究包括：( 胸腺中注射供体细胞或MHC抗原；( 诱导嵌合体和微嵌合体形成；" 基因改造修饰供体MHC抗原；1/4 阻断T细胞辅助刺激信号途径等。而这些方法或者由于手术操作复杂、诱导时间长或者过程本身对患者进一步造成损伤，以及应用效果不稳定等原因而限制了其直接过渡到临床应用。T淋巴细胞是机体细胞免疫的重要执行和调节细胞，是参与同种/异种器官移植急性排斥反应的主要效应细胞，诱导受体T淋巴细胞对供者的特异性细胞免疫耐受是解决器官移植急性排斥反应的最主要最有效手段。
由于免疫干预措施的局限性，诱导异基因组织器官移植（含皮肤移植）终生存活仍然仿佛是童话世界中的海市蜃楼。在大面积深度烧伤患者的临床治疗中，自体皮肤移植仍然是封闭治愈深度烧伤创面的唯一最终有效途径。而大面积烧伤后，封闭烧伤创面的自体皮源往往严重不足，采用皮肤代用品暂时覆盖受损创面便成为烧伤治疗中被迫而必须采取的补救措施。异体（异种）皮由于其生理结构、性能等方面与人体皮肤存在的极大相似性，被认为是皮肤代用品中的首选。但是在其临床应用中，已经发现其存活时间相对较短。在大面积深度烧伤患者治疗过程中，患者微存的少量健康皮肤作为供皮区切取以后，未完全愈合待第二切取时，移植的异体（种）皮多数已被排斥。所以，其自体皮源的供应必然存在或长或短的时相缺隙。
大面积深度烧伤后，机体免疫功能尤其是细胞免疫功能本已严重受抑，采用非选择性的免疫抑制药物延长创面异基因移植皮肤存活时间，将势必进一步加重患者本身的免疫功能抑制，促成感染等其他并发症的发生。因此，采用免疫抑制药物延长烧伤
创面移植皮肤存活时间几乎被视为临床禁忌，探索一种选择性干预和抑制排斥皮肤的移植免疫功能而主要是抑制针对移植皮肤特异性的T细胞功能的治疗措施势在必行。
免疫自稳机制是机体免疫系统恒久存在的的三大原始功能之一。调节性T细胞（Regulatory T cell, Treg）对正常机体中未被胸腺“阴性选择”克隆清除的“自身反应性” T细胞的“休眠状态”的维持和对部分效应性T细胞的功能抑制是个体维持免疫自稳的重要机制之一。通过特异性抗原预先致敏的Treg细胞对效应性T细胞的抑制具有抗原特异性。调节性T细胞虽然在自身免疫性疾病和肿瘤免疫研究领域被发现，但由于其对效应性T细胞的选择性抑制，使其在移植领域的研究和应用越来越受到重视。本课题拟在建立稳定的Treg细胞富集分离方法的基础上，充分探讨Treg细胞对效应性T 细胞的作用机制，同时采用皮肤移植模型，从Treg细胞参与维持正常机体免疫自稳的机制出发，以供体抗原遭遇型(antigen experienced)受体Treg细胞体内应用的方法，选择性抑制移植抗原特异性效应性T 细胞，分析其对受体正常免疫功能的影响及其介导移植免疫耐受的免疫学机制，为推动Treg细胞作为应用性致耐工具细胞奠定实验基础。本项目研究中，我们所获得的主要结果和结论归纳如下：
1． 在Treg细胞分选方法上，通过T细胞纯化柱分离T淋巴细胞，并采用MACS磁板分选装置，以CD8-D&CD25-P组合方式分选CD4+CD25+ Treg细胞是经优化后的分离富集Treg细胞的理想方法。
2． 胸腺微环境是影响Treg细胞发育形成的重要因素， IL-10和TGF-β1是Treg细胞体内外诱导增殖及促生长的细胞因子，以IL-10对Treg细胞的促生长作用更显著。成年期胸腺仍然是培育Treg细胞形成发育的重要载体器官。胸腺切除将导致Treg细胞外周比例的明显下降。
3． Treg细胞能分泌细胞因子IL-10和TGF-β1。其膜表面共刺激分子表达中，CTLA4表达水平明显高于CD28，这种表达特征与效应性T细胞正好相反。CTLA4的高表达可能是Treg细胞施行细胞间接触抑制和其抑制高效性的分子基础。Treg细胞对效应性T细胞的功能抑制有细胞间接触机制和细胞因子依赖机制，但以细胞间接触机制占主导；而细胞因子机制中，IL-10的作用强于TGF-β1。Treg细胞对效应性T细胞的功能抑制具有抗原特异性。
4． Treg细胞对同种及异种混合淋巴细胞反应的抑制呈现明显的细胞剂量效应关系，Treg细胞对同种混合淋巴细胞反应的抑制有明显的剂量饱和特性。在体皮肤移植实验同样证明，Treg细胞应用对介导同种及异种皮肤移植存活时间存在细胞剂量与耐受强度（以平均存活时间表示）的剂量时间依赖关系。
一次性Treg细胞应用对介导二次植皮平均存活时间较不采用任何干预措施所获得的正常对照二次植皮平均存活时间（3-4天）长9-10天。我们推测，Treg应用后，
5． 可能会带来机体naive T细胞向
Transplantation has become a mainstay of therapy for most patients with end-stage organ dysfunction. During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival time has been significantly prolonged, and such survival depends on a number of factors but the most significant of these is the administration of powerful immunosuppressive drugs. Transplantation between genetically disparate individuals (transplantation of an allograft or xenograft) evokes a rapid and potentially destructive immune response that, if left unchecked, can lead to almost complete destruction of the transplanted organ within a matter of days. Administration of immunosuppressive drugs (such as the purine analogue azathioprine, the steroid methylprednisolone, the cyclic peptide cyclosporin A and a variety of anti-lymphocyte antibody preparations) attenuates this response and thus prevents acute graft rejection. However, continued graft survival depends on life-long immunosuppression because, except for a very small number of cases (the majority of which involve liver transplantation and should probably be regarded as a special case), withdrawal of immunosuppression results in re-activation of the rejection response, leading to rapid graft destruction. Although the immunosuppressive drugs that are currently available and very effective in the short term, substantial problems in four specific areas indicate a pressing need to develop alternative and more sophisticated ways of preventing graft rejection. These areas can be summarised as follows: ①chronic graft rejection, ②transplant-associated vasculopathy, ③infection and ④ cancer.
Clinical success continues to be limited by the ongoing need in the majority of patients for nonspecific immunosuppressive therapy that reduces the risk of graft rejection but also brings with it unwanted effects, such as increased susceptibility to infection and malignancy. In addition, the majority of immunosuppressive drugs in current clinical use act by inhibiting T cell activation and thus prevent graft rejection; however, this may be counter-productive, as under appropriate circumstances, T cell activation may lead to the induction of processes facilitating the development of graft-specific tolerance. The final
destruction of an allograft might involve most, or perhaps all, of the cellular and non-cellular components of the immune system, but many studies have shown that T lymphocytes and particularly CD4+ T cells play an essential pivotal role in graft rejection. Therefore, the majority of protocols aimed at providing true transplantation tolerance are designed to tolerise T cells. In order to assess the possibilities for the induction of T-cell tolerance to transplanted organs, it is necessary to consider some fundamental aspects of T-cell function and examine the basis of tolerance to self. That is to say, all strategies for transplantation tolerance must target T cells, and the major aim of transplantation immunology is to develop protocols that prevent immune responses towards the graft but leave the rest of the immune system intact.
Most important of all is that, the immunosuppressive agents currently used in clinical transplantation are non-specific in nature and cannot distinguish between beneficial immune responses against infectious pathogens and destructive immune responses against the graft. Thus, the administration of immunosuppressive drugs necessary to prevent graft rejection can lead to an increased risk of opportunistic infection. While current procedures for burn injury management have improved patient prognosis, increased morbidity and mortality remain major concerns. Thus, identification of the mechanisms responsible for post-burn immune dysfunction and increased susceptibility to subsequent sepsis and multiple organ failure under such conditions are essential for the development of improved treatment modalities.
Thermal injury induces a
由于免疫干预措施的局限性，诱导异基因组织器官移植（含皮肤移植）终生存活仍然仿佛是童话世界中的海市蜃楼。在大面积深度烧伤患者的临床治疗中，自体皮肤移植仍然是封闭治愈深度烧伤创面的唯一最终有效途径。而大面积烧伤后，封闭烧伤创面的自体皮源往往严重不足，采用皮肤代用品暂时覆盖受损创面便成为烧伤治疗中被迫而必须采取的补救措施。异体（异种）皮由于其生理结构、性能等方面与人体皮肤存在的极大相似性，被认为是皮肤代用品中的首选。但是在其临床应用中，已经发现其存活时间相对较短。在大面积深度烧伤患者治疗过程中，患者微存的少量健康皮肤作为供皮区切取以后，未完全愈合待第二切取时，移植的异体（种）皮多数已被排斥。所以，其自体皮源的供应必然存在或长或短的时相缺隙。
大面积深度烧伤后，机体免疫功能尤其是细胞免疫功能本已严重受抑，采用非选择性的免疫抑制药物延长创面异基因移植皮肤存活时间，将势必进一步加重患者本身的免疫功能抑制，促成感染等其他并发症的发生。因此，采用免疫抑制药物延长烧伤
创面移植皮肤存活时间几乎被视为临床禁忌，探索一种选择性干预和抑制排斥皮肤的移植免疫功能而主要是抑制针对移植皮肤特异性的T细胞功能的治疗措施势在必行。
免疫自稳机制是机体免疫系统恒久存在的的三大原始功能之一。调节性T细胞（Regulatory T cell, Treg）对正常机体中未被胸腺“阴性选择”克隆清除的“自身反应性” T细胞的“休眠状态”的维持和对部分效应性T细胞的功能抑制是个体维持免疫自稳的重要机制之一。通过特异性抗原预先致敏的Treg细胞对效应性T细胞的抑制具有抗原特异性。调节性T细胞虽然在自身免疫性疾病和肿瘤免疫研究领域被发现，但由于其对效应性T细胞的选择性抑制，使其在移植领域的研究和应用越来越受到重视。本课题拟在建立稳定的Treg细胞富集分离方法的基础上，充分探讨Treg细胞对效应性T 细胞的作用机制，同时采用皮肤移植模型，从Treg细胞参与维持正常机体免疫自稳的机制出发，以供体抗原遭遇型(antigen experienced)受体Treg细胞体内应用的方法，选择性抑制移植抗原特异性效应性T 细胞，分析其对受体正常免疫功能的影响及其介导移植免疫耐受的免疫学机制，为推动Treg细胞作为应用性致耐工具细胞奠定实验基础。本项目研究中，我们所获得的主要结果和结论归纳如下：
1． 在Treg细胞分选方法上，通过T细胞纯化柱分离T淋巴细胞，并采用MACS磁板分选装置，以CD8-D&CD25-P组合方式分选CD4+CD25+ Treg细胞是经优化后的分离富集Treg细胞的理想方法。
2． 胸腺微环境是影响Treg细胞发育形成的重要因素， IL-10和TGF-β1是Treg细胞体内外诱导增殖及促生长的细胞因子，以IL-10对Treg细胞的促生长作用更显著。成年期胸腺仍然是培育Treg细胞形成发育的重要载体器官。胸腺切除将导致Treg细胞外周比例的明显下降。
3． Treg细胞能分泌细胞因子IL-10和TGF-β1。其膜表面共刺激分子表达中，CTLA4表达水平明显高于CD28，这种表达特征与效应性T细胞正好相反。CTLA4的高表达可能是Treg细胞施行细胞间接触抑制和其抑制高效性的分子基础。Treg细胞对效应性T细胞的功能抑制有细胞间接触机制和细胞因子依赖机制，但以细胞间接触机制占主导；而细胞因子机制中，IL-10的作用强于TGF-β1。Treg细胞对效应性T细胞的功能抑制具有抗原特异性。
4． Treg细胞对同种及异种混合淋巴细胞反应的抑制呈现明显的细胞剂量效应关系，Treg细胞对同种混合淋巴细胞反应的抑制有明显的剂量饱和特性。在体皮肤移植实验同样证明，Treg细胞应用对介导同种及异种皮肤移植存活时间存在细胞剂量与耐受强度（以平均存活时间表示）的剂量时间依赖关系。
一次性Treg细胞应用对介导二次植皮平均存活时间较不采用任何干预措施所获得的正常对照二次植皮平均存活时间（3-4天）长9-10天。我们推测，Treg应用后，
5． 可能会带来机体naive T细胞向
Transplantation has become a mainstay of therapy for most patients with end-stage organ dysfunction. During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival time has been significantly prolonged, and such survival depends on a number of factors but the most significant of these is the administration of powerful immunosuppressive drugs. Transplantation between genetically disparate individuals (transplantation of an allograft or xenograft) evokes a rapid and potentially destructive immune response that, if left unchecked, can lead to almost complete destruction of the transplanted organ within a matter of days. Administration of immunosuppressive drugs (such as the purine analogue azathioprine, the steroid methylprednisolone, the cyclic peptide cyclosporin A and a variety of anti-lymphocyte antibody preparations) attenuates this response and thus prevents acute graft rejection. However, continued graft survival depends on life-long immunosuppression because, except for a very small number of cases (the majority of which involve liver transplantation and should probably be regarded as a special case), withdrawal of immunosuppression results in re-activation of the rejection response, leading to rapid graft destruction. Although the immunosuppressive drugs that are currently available and very effective in the short term, substantial problems in four specific areas indicate a pressing need to develop alternative and more sophisticated ways of preventing graft rejection. These areas can be summarised as follows: ①chronic graft rejection, ②transplant-associated vasculopathy, ③infection and ④ cancer.
Clinical success continues to be limited by the ongoing need in the majority of patients for nonspecific immunosuppressive therapy that reduces the risk of graft rejection but also brings with it unwanted effects, such as increased susceptibility to infection and malignancy. In addition, the majority of immunosuppressive drugs in current clinical use act by inhibiting T cell activation and thus prevent graft rejection; however, this may be counter-productive, as under appropriate circumstances, T cell activation may lead to the induction of processes facilitating the development of graft-specific tolerance. The final
destruction of an allograft might involve most, or perhaps all, of the cellular and non-cellular components of the immune system, but many studies have shown that T lymphocytes and particularly CD4+ T cells play an essential pivotal role in graft rejection. Therefore, the majority of protocols aimed at providing true transplantation tolerance are designed to tolerise T cells. In order to assess the possibilities for the induction of T-cell tolerance to transplanted organs, it is necessary to consider some fundamental aspects of T-cell function and examine the basis of tolerance to self. That is to say, all strategies for transplantation tolerance must target T cells, and the major aim of transplantation immunology is to develop protocols that prevent immune responses towards the graft but leave the rest of the immune system intact.
Most important of all is that, the immunosuppressive agents currently used in clinical transplantation are non-specific in nature and cannot distinguish between beneficial immune responses against infectious pathogens and destructive immune responses against the graft. Thus, the administration of immunosuppressive drugs necessary to prevent graft rejection can lead to an increased risk of opportunistic infection. While current procedures for burn injury management have improved patient prognosis, increased morbidity and mortality remain major concerns. Thus, identification of the mechanisms responsible for post-burn immune dysfunction and increased susceptibility to subsequent sepsis and multiple organ failure under such conditions are essential for the development of improved treatment modalities.
Thermal injury induces a
引文
1. Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nature Rev Immunology, 2001; 1(12): 233-239
2. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. N. Engl. J. Med. 1998; 3391905-1913.
3. Jeffrey AB, Matthews JB, Krensky AM. The Immune Tolerance Network: The "Holy Grail" Comes to the Clinic. J Am Soc Nephrol, 2000; 11: 2141-2146.
4. Burnet FM, Fenner F. The Production of Antibodies 2nd edn (Macmillan, Melbourne 1949).
5. Stone HB, Owings JC, Gey GO. Transplantation of living grafts of thyroid and parathyroid glands. Ann. Surg. 1934;100: 613-628.
6. Barker CF, Billingham RE. The role of afferent lymphatics in the rejection of skin homografts. J. Exp.Med. 1968;128: 197-221.
7. Lafferty KJ, Prowse SJ, Simeonovic CJ. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu. Rev. Immunol. 1983;1:143-173.
8. Billingham RE. Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature .1953; 172:603-606.
9. Cobbold SP, Martin G, Qin S. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature. 1986; 323:164-166.
10. Sykes M. Mixed chimerism and transplant tolerance. Immunity, 2001; 14:417-424.
11. Storb R, Yu C, Barnett T, et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation. Blood. 1999; 94:1131-1136.
12. Cho CS, Fechner JH Jr, Knechtle SJ, T-cell depletion as a means of achieving tolerance. Curr Opin Organ Transplant .2000; 5:96-102.
13. 刘燕明. 免疫系统的原始功能. 免疫学杂志,1995;11(1):61-63.
14. Gavin MA, Clarke SR, Negrou E, et al. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vitro.Nature Immunology, 2002; 3(1):33-41.
15. 杨尚琪.诱导器官移植免疫耐受的新进展. 肾脏病与透析肾移植杂志, 2000; 9(4):385-387
16. Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity, Curr. Opin. Immunol. 1998;10: 656-662.
17. Gleeson PA., Toh BH. van Driel I.R., Organ-specific autoimmunity induced by lymphopenia, Immunol. Rev. 1996;149: 97-125.
18. Saoudi A, Seddon B, Heath V, et al The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset, Immunol. Rev. 1996;149:195-216.
19. Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential, J. Exp. Med. 1993;177: 627-636.
20. Seddon B, Mason D. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+CD45RCcells and CD4+CD8- thymocytes, J. Exp. Med. 1999;189: 279-288.
21. Rossini AA, Mordes JP, Greiner DL. The pathogenesis of autoimmune diabetes mellitus, Curr. Opin. Immunol. 1989; 2: 598-603.
22. Whalen BJ, Greiner DL, Mordes JP, et al. Adoptive transfer of autoimmune diabetes mellitus to athymic rats: synergy of CD4+ and CD8+ T cells and prevention by RT6+ T cells, J. Autoimmun. 1994;7 : 819-831.
23. Seddon B, Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity, J. Exp. Med. 1999;189: 877-882.
24. 黎鳌,烧伤防治研究的展望?中华创伤杂志,1995;5:23-27
25. 黎鳌,我国烧伤救治研究的过去?现在和未来?中华烧伤杂志,2001;1:3-5
26. 郑峻松,吴军,彭代智等?严重烧伤后小鼠脾脏T淋巴细胞跨膜信号转导的改变与IL-2?IL-10分泌?2000;16(6):352-354
27. 黎鳌,杨宗城?《黎鳌烧伤学》,上海科学技术出版社:318-343
28. Bjerkans. Altered neutrophil functions in patients with large burms. Blood cell,1990;12(7):47-49.
29. O'Sullivan, James AL, Douglas HL, et al. Major injure leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin- 12 production associated with decreased resistance to infection. Ann Surg, 1995; 222: 482-492
30. Read S., Mauze S., Asseman C. et al. CD38+ CD45RBlow CD4+ T cells: a population
of T cells with immune regulatory activities in vitro, Eur. J. Immunol. 1998; 28: 3435-3447.
31. Stephens LA, Mason D. CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations, J. Immunol. 2000;165: 3105-3110.
32. 龙振洲,丁桂风主编,《免疫学实验技术》,北京医科大学出版社,1988,P128?
33. 李家增,王鸿利,韩忠朝主编,《血液免疫学》,上海科学技术出版社,1997,P58-63?
34. 薛庆善主编,《体外培养的原理与技术》,科学出版社,2001,P176-229?
35. Jian-Guo Chai1, Julia YS, Tsang, RL, et al. CD4+CD25+ T cells as immunoregulatory T cells in vitro. Eur. J. Immunol. 2002; 32: 2365-2375
36. Shevach EM. Regulatory T cells in autoimmunity. Ann Rev Immunol, 2000;18:423-449.
37. Suri-Payer E, Amar AZ, Thornton A, et al. CD4+25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 1998;160: 1212-1218.
38. Masaki H, Cherry IK, Masanori N, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigen in vivo. J Immunol, 2001;166:3789-3796.
39. Yamagiwa S, Gray J, Hashimoto S, et al. A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheralblood. J Immunol, 2001;166:7282-7289.
40. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunological self-tolerance maintained by activated T cells expressing IL-2 receptor α chain. Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995,155: 1151-1164.
42. Asano M, Toda M, Sakaguchi N, et al. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 1996;184: 387-396.
43. Itoh M, Takahishi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunological self-tolerance. J. Immunol. 1999;162: 5317-5326.
44. Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12: 431-440.
45. Seddon B, Mason D. The third function of the thymus. Immunol Today, 2000;21(2):95-99.
46. Thornton AN, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 1998;188:287-296.
47. Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic selftolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 1998;10:1969-1980.
48. Thornton AN, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 2000;164: 183-190.
49. Piccirillo CA, and Shevach EM. Cutting Edge: Control of CD8+ T cell activation by CD4+25+ immunoregulatory cells. J. Immunol. 2001;167: 1137-1140.
50. Greenwald RJ, Boussiotis VA, Lorsbach RB, et al. CTLA-4 regulates induction of anergy in vivo. Immunity. 2001;14: 145-155.
51. Hironori M, Fujimoto S,Green MI. Suppressor T cells regulate the nonanergic T cell population that remains after peripheral tolerance is induced to the Mls-1 antigen in T cell receptor Vb8.1-transgenic mice. Proc.Natl. Acad. Sci. USA2000;97: 13257-13262.
52. Vendetti S, Chai JG, Dyson J, et al. Anergic T cells inhibit the antigen presenting function of dendritic cells. J. Immunol. 2000;165: 175-181.
53. Jonuleit H, Schmitt E, Schuler G, et al. Induction of interleukin 10-producing, nonprolifrating CD4+ T cells with regulatroy properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 2000;192: 1213-1222.
54. Modigliani Y, Coutinho A, Pereira P, et al. Establishment of tissue-specific tolerance is driven by regulatory T cells selected by thymic epithelium, Eur. J. Immunol.1996;26:1807-1815.
55. Saoudi A, Seddon B, Fowell D, et al. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients, J. Exp. Med. 1996; 184: 2393-2398.
56. Papiernik M, de Moraes ML, Pontoux C, et al. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency, Int. Immunol. 1998;10:371-378.
57. Smith KM, Olson DC, Hirose R, et al. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance, Int. Immunol. 1997;9: 1355-1365.
58. Seddon B, Saoudi A, Nicholson M, et al. CD4+CD8- thymocytes that express L-selectin protect rats from diabetes upon adoptive transfer, Eur. J. Immunol. 1996;26: 2702-2708.
59. Takahashi T, Tagami T, Yamazaki S, et al. Immunological self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp.Med. 2000;192: 303-309.
60. Cederbom L, Hakan H, Ivars F. CD4+CD25+ regulatory cells down-regulate co-stimulatroy molecules on antigenpresenting cells. Eur. J. Immunol. 2000; 30: 1538-1543.
61. Chen W, Jin W, Wahl SM. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor β (TGF β) production by murine CD4+ T cells. J. Exp. Med. 1998;188: 1849-1857.
62. Read S, Malmstrom Y, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J Exp Med. 2000;192: 295-302.
63. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.J. Exp Med. 2000;192:303-331.
64. Kuniyasu Y, Takahashi T, Itoh M, et al. Naturally anergic and suppressive CD251 CD41 T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12:1145-1155.
65. Akira Suto, Hiroshi Nakajima, Kei Ikeda, Shuichi Kubo,et al. CD4+CD25+ T-cell development is regulated by at least 2 distinct mechanisms. Blood. 2002;99: 555-560
66. 王劲, 99Tcm~锝(99)标记白细胞:急性实验性胰腺炎时确定白细胞对局部及全身作用的一种新方法?肝胆外科杂志,1998;6(6):329-330
67. 万叔良, 何红兵, 潘明新等,99Tcm~锝(99m)标记血小板检测内皮化人工血管内皮细胞抗血小板粘附聚集功能的研究 ?中华实验外科杂志,2001;18(3):221-223
68. 颜学先,李少林?五价锝标记DMSA药盒制备方法的评价与优化?核技术,1999;22(5):259-262
69. Herman Waldmann,Therapeutic approaches for transplantation,Curr Opin Immunol..2001; 13:606-610
70. Sonntag KC, Emery DW, Yasumoto A, et al. Tolerance to solid organ transplants
through transfer of MHC class II genes. J Clin Invest. 2001; 107:65-71.
71. Knechtle SJ. Knowledge about transplantation tolerance gained in primates. Curr Opin Immunol 2000; 12:552-556.
72. Kawai T, Andrews D, Colvin RB, et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000; 6:114-118.
73. Buhler L, Alwayn IP, Appel JZ, et al.Anti-CD154 monoclonal antibody and thromboembolism. Transplantation . 2001; 71:491-501.
74. Cho CS, Fechner JH Jr, Knechtle SJ. T-cell depletion as a means of achieving tolerance. Curr Opin Organ Transplant. 2000; 5:96-102.
75. Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N. Engl. J. Med. 1963;268:1315-1323 .
76. Li B, Hartono C, Ding R, Sharma VK, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. New Engl J Med. 2001; 344:947-954.
77. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology, 1993;17: 1127-1157
78. Devlin J, Doherty D, Thomson L, et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology, 1998; 27: 926-933
79. Li B, Hartono C, Ding R, Sharma VK, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. New Engl J Med. 2001; 344:947-954.
80. Soulillou JP. Immune monitoring for rejection of kidney transplants. New Engl J Med. 2001; 344:1006-1007.
81. Keck T, Lindemann J ,Kuhnemann S, et al. Healing of composite chondrocutaneous auricular grafts covered by skin flaps in nasal reconstructive surgery. Laryngoscope , 2003; 113(2): 248-53.
82. Hamoen KE, Morgan JR. Transient hyperproliferation of a transgenic human epidermis expressing hepatocyte growth factor. Cell Transplantation,2002; 11(4): 385-95.
83. Sebille F, Brouard S, Petzold T, et al. Tolerance induction in rats, using a combination of anti-CD154 and donor splenocytes, given once on the day of transplantation.
Transplantation, 2003; 75(2): 169-72.
84. Y Zhao, K Swenson, JJ Sergio, et al. Skin graft tolerance across a discordant xenogeneic barrier, Nat. Med. 1996; 2: 1211-1216.
85. Steinmuller, D. Immunization with skin isografts taken from tolerant mice. Science. 1967; 158: 127-129.
86. Lafferty KJ, Prowse SJ, Simeonovic CJ. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu. Rev. Immunol. 1983; 1:143-173.
87. Bumgardner GL, Li J, Heininger M, et al. In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model. Transplantation , 1998;65: 47-52.
88. Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic ignorance of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med. 2000; 6: 686-688.
89. Terakura M. Lymphoid/non-lymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct BM. Transplantation , 1998; 66: 350-357.
90. Dong C, Flavell RA . TH1 and TH2 cells. Curr Opin Hematol, 2001; 8:47-51.
91. Erbagci AB, Herken H, Koyluoglu O, et al. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomathology and responsiveness to risperidone treatment. Mediators Inflamm, 2001; 10:109-115.
92. Esterling BA, Kiecolt-Glaser JK, Bodnar JC, et al. Chronic stress, social support, and persistent alterations in the natural killer cell response to cytokines in older adults. Health Psycho,l 1994;13:291-298.
93. Gollob KJ, Dutra WO, Coffman RL. Early message expression of interleukin-4 and interferon-gamma, but not of interleukin-2 and interleukin-10, reflects later polarization of primary CD4- T cell cultures. Eur J Immunol, 1996; 26:1565-1570.
94. Haack M, Hinze-Selch D, Fenzel T, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission Effects of confounding factors and diagnosis. J Psychiatr Res, 1999; 33:407-418.
95. Heiser P, Dickhaus B, Schreiber W, et al. White blood cells and cortisol after sleep deprivation and recovery sleep in humans. Eur Arch Psychiatry Clin Neurosci ,2000; 250:16-23.
96. Lenardo M. Mature T lymphocyte apoptosis -Immune regulation in a dynamic and
unpredictable antigenic environment. Ann. Rev. Immunol. 1999; 17:221-253 .
97. Griffith TS. Fas-Ligand-induced apoptosis as a mechanism of immune privilege. Science,, 1995; 270:1189-1191.
98. Stuart PM. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J. Clin. Invest, 1997; 99: 396-402.
99. Li Y. Global immunosuppression prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nature Med, 1999; 5:1298-1302.
100.Wells AD. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nature Med, 1999; 5:1303-1307 .
101.Sakaguchi S. Regulatory T cells mediating compromises between host and parasite. Nature Immunology, 2003; 4(1):10-11
2. Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. N. Engl. J. Med. 1998; 3391905-1913.
3. Jeffrey AB, Matthews JB, Krensky AM. The Immune Tolerance Network: The "Holy Grail" Comes to the Clinic. J Am Soc Nephrol, 2000; 11: 2141-2146.
4. Burnet FM, Fenner F. The Production of Antibodies 2nd edn (Macmillan, Melbourne 1949).
5. Stone HB, Owings JC, Gey GO. Transplantation of living grafts of thyroid and parathyroid glands. Ann. Surg. 1934;100: 613-628.
6. Barker CF, Billingham RE. The role of afferent lymphatics in the rejection of skin homografts. J. Exp.Med. 1968;128: 197-221.
7. Lafferty KJ, Prowse SJ, Simeonovic CJ. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu. Rev. Immunol. 1983;1:143-173.
8. Billingham RE. Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature .1953; 172:603-606.
9. Cobbold SP, Martin G, Qin S. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature. 1986; 323:164-166.
10. Sykes M. Mixed chimerism and transplant tolerance. Immunity, 2001; 14:417-424.
11. Storb R, Yu C, Barnett T, et al. Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation. Blood. 1999; 94:1131-1136.
12. Cho CS, Fechner JH Jr, Knechtle SJ, T-cell depletion as a means of achieving tolerance. Curr Opin Organ Transplant .2000; 5:96-102.
13. 刘燕明. 免疫系统的原始功能. 免疫学杂志,1995;11(1):61-63.
14. Gavin MA, Clarke SR, Negrou E, et al. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vitro.Nature Immunology, 2002; 3(1):33-41.
15. 杨尚琪.诱导器官移植免疫耐受的新进展. 肾脏病与透析肾移植杂志, 2000; 9(4):385-387
16. Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity, Curr. Opin. Immunol. 1998;10: 656-662.
17. Gleeson PA., Toh BH. van Driel I.R., Organ-specific autoimmunity induced by lymphopenia, Immunol. Rev. 1996;149: 97-125.
18. Saoudi A, Seddon B, Heath V, et al The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset, Immunol. Rev. 1996;149:195-216.
19. Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential, J. Exp. Med. 1993;177: 627-636.
20. Seddon B, Mason D. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+CD45RCcells and CD4+CD8- thymocytes, J. Exp. Med. 1999;189: 279-288.
21. Rossini AA, Mordes JP, Greiner DL. The pathogenesis of autoimmune diabetes mellitus, Curr. Opin. Immunol. 1989; 2: 598-603.
22. Whalen BJ, Greiner DL, Mordes JP, et al. Adoptive transfer of autoimmune diabetes mellitus to athymic rats: synergy of CD4+ and CD8+ T cells and prevention by RT6+ T cells, J. Autoimmun. 1994;7 : 819-831.
23. Seddon B, Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity, J. Exp. Med. 1999;189: 877-882.
24. 黎鳌,烧伤防治研究的展望?中华创伤杂志,1995;5:23-27
25. 黎鳌,我国烧伤救治研究的过去?现在和未来?中华烧伤杂志,2001;1:3-5
26. 郑峻松,吴军,彭代智等?严重烧伤后小鼠脾脏T淋巴细胞跨膜信号转导的改变与IL-2?IL-10分泌?2000;16(6):352-354
27. 黎鳌,杨宗城?《黎鳌烧伤学》,上海科学技术出版社:318-343
28. Bjerkans. Altered neutrophil functions in patients with large burms. Blood cell,1990;12(7):47-49.
29. O'Sullivan, James AL, Douglas HL, et al. Major injure leads to predominance of the T helper-2 lymphocyte phenotype and diminished interleukin- 12 production associated with decreased resistance to infection. Ann Surg, 1995; 222: 482-492
30. Read S., Mauze S., Asseman C. et al. CD38+ CD45RBlow CD4+ T cells: a population
of T cells with immune regulatory activities in vitro, Eur. J. Immunol. 1998; 28: 3435-3447.
31. Stephens LA, Mason D. CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations, J. Immunol. 2000;165: 3105-3110.
32. 龙振洲,丁桂风主编,《免疫学实验技术》,北京医科大学出版社,1988,P128?
33. 李家增,王鸿利,韩忠朝主编,《血液免疫学》,上海科学技术出版社,1997,P58-63?
34. 薛庆善主编,《体外培养的原理与技术》,科学出版社,2001,P176-229?
35. Jian-Guo Chai1, Julia YS, Tsang, RL, et al. CD4+CD25+ T cells as immunoregulatory T cells in vitro. Eur. J. Immunol. 2002; 32: 2365-2375
36. Shevach EM. Regulatory T cells in autoimmunity. Ann Rev Immunol, 2000;18:423-449.
37. Suri-Payer E, Amar AZ, Thornton A, et al. CD4+25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 1998;160: 1212-1218.
38. Masaki H, Cherry IK, Masanori N, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigen in vivo. J Immunol, 2001;166:3789-3796.
39. Yamagiwa S, Gray J, Hashimoto S, et al. A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheralblood. J Immunol, 2001;166:7282-7289.
40. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunological self-tolerance maintained by activated T cells expressing IL-2 receptor α chain. Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995,155: 1151-1164.
42. Asano M, Toda M, Sakaguchi N, et al. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 1996;184: 387-396.
43. Itoh M, Takahishi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunological self-tolerance. J. Immunol. 1999;162: 5317-5326.
44. Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12: 431-440.
45. Seddon B, Mason D. The third function of the thymus. Immunol Today, 2000;21(2):95-99.
46. Thornton AN, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 1998;188:287-296.
47. Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic selftolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 1998;10:1969-1980.
48. Thornton AN, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J. Immunol. 2000;164: 183-190.
49. Piccirillo CA, and Shevach EM. Cutting Edge: Control of CD8+ T cell activation by CD4+25+ immunoregulatory cells. J. Immunol. 2001;167: 1137-1140.
50. Greenwald RJ, Boussiotis VA, Lorsbach RB, et al. CTLA-4 regulates induction of anergy in vivo. Immunity. 2001;14: 145-155.
51. Hironori M, Fujimoto S,Green MI. Suppressor T cells regulate the nonanergic T cell population that remains after peripheral tolerance is induced to the Mls-1 antigen in T cell receptor Vb8.1-transgenic mice. Proc.Natl. Acad. Sci. USA2000;97: 13257-13262.
52. Vendetti S, Chai JG, Dyson J, et al. Anergic T cells inhibit the antigen presenting function of dendritic cells. J. Immunol. 2000;165: 175-181.
53. Jonuleit H, Schmitt E, Schuler G, et al. Induction of interleukin 10-producing, nonprolifrating CD4+ T cells with regulatroy properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 2000;192: 1213-1222.
54. Modigliani Y, Coutinho A, Pereira P, et al. Establishment of tissue-specific tolerance is driven by regulatory T cells selected by thymic epithelium, Eur. J. Immunol.1996;26:1807-1815.
55. Saoudi A, Seddon B, Fowell D, et al. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients, J. Exp. Med. 1996; 184: 2393-2398.
56. Papiernik M, de Moraes ML, Pontoux C, et al. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency, Int. Immunol. 1998;10:371-378.
57. Smith KM, Olson DC, Hirose R, et al. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance, Int. Immunol. 1997;9: 1355-1365.
58. Seddon B, Saoudi A, Nicholson M, et al. CD4+CD8- thymocytes that express L-selectin protect rats from diabetes upon adoptive transfer, Eur. J. Immunol. 1996;26: 2702-2708.
59. Takahashi T, Tagami T, Yamazaki S, et al. Immunological self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp.Med. 2000;192: 303-309.
60. Cederbom L, Hakan H, Ivars F. CD4+CD25+ regulatory cells down-regulate co-stimulatroy molecules on antigenpresenting cells. Eur. J. Immunol. 2000; 30: 1538-1543.
61. Chen W, Jin W, Wahl SM. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor β (TGF β) production by murine CD4+ T cells. J. Exp. Med. 1998;188: 1849-1857.
62. Read S, Malmstrom Y, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J Exp Med. 2000;192: 295-302.
63. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.J. Exp Med. 2000;192:303-331.
64. Kuniyasu Y, Takahashi T, Itoh M, et al. Naturally anergic and suppressive CD251 CD41 T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12:1145-1155.
65. Akira Suto, Hiroshi Nakajima, Kei Ikeda, Shuichi Kubo,et al. CD4+CD25+ T-cell development is regulated by at least 2 distinct mechanisms. Blood. 2002;99: 555-560
66. 王劲, 99Tcm~锝(99)标记白细胞:急性实验性胰腺炎时确定白细胞对局部及全身作用的一种新方法?肝胆外科杂志,1998;6(6):329-330
67. 万叔良, 何红兵, 潘明新等,99Tcm~锝(99m)标记血小板检测内皮化人工血管内皮细胞抗血小板粘附聚集功能的研究 ?中华实验外科杂志,2001;18(3):221-223
68. 颜学先,李少林?五价锝标记DMSA药盒制备方法的评价与优化?核技术,1999;22(5):259-262
69. Herman Waldmann,Therapeutic approaches for transplantation,Curr Opin Immunol..2001; 13:606-610
70. Sonntag KC, Emery DW, Yasumoto A, et al. Tolerance to solid organ transplants
through transfer of MHC class II genes. J Clin Invest. 2001; 107:65-71.
71. Knechtle SJ. Knowledge about transplantation tolerance gained in primates. Curr Opin Immunol 2000; 12:552-556.
72. Kawai T, Andrews D, Colvin RB, et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000; 6:114-118.
73. Buhler L, Alwayn IP, Appel JZ, et al.Anti-CD154 monoclonal antibody and thromboembolism. Transplantation . 2001; 71:491-501.
74. Cho CS, Fechner JH Jr, Knechtle SJ. T-cell depletion as a means of achieving tolerance. Curr Opin Organ Transplant. 2000; 5:96-102.
75. Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N. Engl. J. Med. 1963;268:1315-1323 .
76. Li B, Hartono C, Ding R, Sharma VK, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. New Engl J Med. 2001; 344:947-954.
77. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology, 1993;17: 1127-1157
78. Devlin J, Doherty D, Thomson L, et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology, 1998; 27: 926-933
79. Li B, Hartono C, Ding R, Sharma VK, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. New Engl J Med. 2001; 344:947-954.
80. Soulillou JP. Immune monitoring for rejection of kidney transplants. New Engl J Med. 2001; 344:1006-1007.
81. Keck T, Lindemann J ,Kuhnemann S, et al. Healing of composite chondrocutaneous auricular grafts covered by skin flaps in nasal reconstructive surgery. Laryngoscope , 2003; 113(2): 248-53.
82. Hamoen KE, Morgan JR. Transient hyperproliferation of a transgenic human epidermis expressing hepatocyte growth factor. Cell Transplantation,2002; 11(4): 385-95.
83. Sebille F, Brouard S, Petzold T, et al. Tolerance induction in rats, using a combination of anti-CD154 and donor splenocytes, given once on the day of transplantation.
Transplantation, 2003; 75(2): 169-72.
84. Y Zhao, K Swenson, JJ Sergio, et al. Skin graft tolerance across a discordant xenogeneic barrier, Nat. Med. 1996; 2: 1211-1216.
85. Steinmuller, D. Immunization with skin isografts taken from tolerant mice. Science. 1967; 158: 127-129.
86. Lafferty KJ, Prowse SJ, Simeonovic CJ. Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu. Rev. Immunol. 1983; 1:143-173.
87. Bumgardner GL, Li J, Heininger M, et al. In vivo immunogenicity of purified allogeneic hepatocytes in a murine hepatocyte transplant model. Transplantation , 1998;65: 47-52.
88. Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic ignorance of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med. 2000; 6: 686-688.
89. Terakura M. Lymphoid/non-lymphoid compartmentalization of donor leukocyte chimerism in rat recipients of heart allografts, with or without adjunct BM. Transplantation , 1998; 66: 350-357.
90. Dong C, Flavell RA . TH1 and TH2 cells. Curr Opin Hematol, 2001; 8:47-51.
91. Erbagci AB, Herken H, Koyluoglu O, et al. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomathology and responsiveness to risperidone treatment. Mediators Inflamm, 2001; 10:109-115.
92. Esterling BA, Kiecolt-Glaser JK, Bodnar JC, et al. Chronic stress, social support, and persistent alterations in the natural killer cell response to cytokines in older adults. Health Psycho,l 1994;13:291-298.
93. Gollob KJ, Dutra WO, Coffman RL. Early message expression of interleukin-4 and interferon-gamma, but not of interleukin-2 and interleukin-10, reflects later polarization of primary CD4- T cell cultures. Eur J Immunol, 1996; 26:1565-1570.
94. Haack M, Hinze-Selch D, Fenzel T, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission Effects of confounding factors and diagnosis. J Psychiatr Res, 1999; 33:407-418.
95. Heiser P, Dickhaus B, Schreiber W, et al. White blood cells and cortisol after sleep deprivation and recovery sleep in humans. Eur Arch Psychiatry Clin Neurosci ,2000; 250:16-23.
96. Lenardo M. Mature T lymphocyte apoptosis -Immune regulation in a dynamic and
unpredictable antigenic environment. Ann. Rev. Immunol. 1999; 17:221-253 .
97. Griffith TS. Fas-Ligand-induced apoptosis as a mechanism of immune privilege. Science,, 1995; 270:1189-1191.
98. Stuart PM. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J. Clin. Invest, 1997; 99: 396-402.
99. Li Y. Global immunosuppression prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nature Med, 1999; 5:1298-1302.
100.Wells AD. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nature Med, 1999; 5:1303-1307 .
101.Sakaguchi S. Regulatory T cells mediating compromises between host and parasite. Nature Immunology, 2003; 4(1):10-11
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