雷帕霉素对小鼠记忆T细胞的体外作用
|
摘要
第一部分建立小鼠皮肤移植排斥模型稳定获得记忆T细胞
目的:建立一种稳定的通过小鼠皮肤移植获得小鼠记忆T细胞的方法,为研究药物对小鼠记忆T细胞的体外作用做准备。
方法:以C57BL/6小鼠为受者、DBA╱2小鼠为供者行皮肤移植;同时行C57BL/6小鼠行同种同系皮肤移植做对照。术后1-8周,每周取小鼠脾脏,使用流式细胞仪检测所有受体鼠脾单个核细胞悬液中记忆T细胞的比例(n=6)。
结果:(1)同种异系皮肤移植组:术后第4周的C57BL/6小鼠脾单个核细胞悬液中记忆T细胞的比例较术后1-3周显著增多(P＜0.01);术后5-8周的记忆T细胞比例较术后第4周显著增多(P＜0.01);术后1-3周小鼠记忆T细胞比例无差异(P＞0.05);术后5-8周小鼠记忆T细胞比例无差异(P＞0.05)。(2)同种同系皮肤移植组:术后8周,每周产生的记忆T细胞比例无差异(P＞0.05)。
结论:接受同种异系皮肤抗原刺激4-5周后,小鼠记忆T细胞发生稳态增殖,此模型可以稳定的获得小鼠记忆T细胞。
第二部分雷帕霉素对小鼠记忆T细胞的体外作用
目的:探讨雷帕霉素对小鼠记忆T细胞的体外生长及白介素-2(IL-2)表达的影响,比较其与初始T细胞对雷帕霉素的敏感性差异,并且初步探讨雷帕霉素对小鼠记忆T细胞抑制作用的机制。
方法:取6周龄以下的C57BL/6小鼠脾脏制备成脾单个核细胞,使用免疫磁珠法分选出小鼠初始T淋巴细胞;取第一部分实验中经过同种异系皮肤移植存活6周以上的C57BL/6小鼠,荧光激活细胞分类术(FACS fluorescence-activated cell sorting)分选出小鼠记忆T细胞。将分选出的小鼠初始和记忆T细胞分别加入0ng/ml、10ng/ml、20ng/ml、30ng/ml梯度浓度的雷帕霉素培养液培养72h后,采用MTT法及Elisa法测定各组细胞的生长情况及IL-2表达情况。同样于72小时后测定10ng/ml雷帕霉素浓度组及对照组(0ng/ml)小鼠记忆T细胞细胞周期的变化,并且使用RT-PCR检测其IL-2R(α、β、γ亚基)mRNA表达情况。
结果:用雷帕霉素培养液培养细胞时,小鼠初始和记忆T细胞生长及IL-2的表达均受到抑制(P＜0.01);随药物浓度增加,细胞生长及IL-2表达受抑制越明显(P＜0.01);同浓度雷帕霉素对于记忆T细胞的生长及IL-2的表达的抑制程度均较初始T细胞弱(P＜0.01);细胞周期检测结果示,实验组与对照组相比,G_0G_1期细胞的比例升高(P＜0.01),S期降低(P＜0.01)。RT-PCR结果显示实验组与对照组IL-2R(α、β、γ亚基)mRNA的表达均有显著性差异(P＜0.01)。
结论:在体外雷帕霉素对小鼠初始和记忆T细胞的生长、IL-2的表达起抑制作用,且随浓度增加,抑制作用增强;且雷帕霉素对小鼠记忆T细胞的抑制作用程度较初始T细胞弱。雷帕霉素通过抑制小鼠记忆T细胞的IL-2R(α、β、γ亚基)及IL-2的表达,并且阻滞其细胞周期来抑制其生长。
Effects of rapamycin on mouse memory T cells in vitro
PART ONE Proliferation of memory T cells in mice by rejection after skin transplant model
Objective To harvest a stable proliferation of memory T cells by T cell proliferation in C57BL/6 mice with skin transplant model.To prepare for the drug effect on the cell in vitro.
Methods We transplanted DBA/2 donors'skin to C57BL/6 recipients. At the same time,transplanted C57BL/6 donors'skin to C57BL/6 hosts as control.The proportion of memory T cells in SPM(spleen mononuclearcell)from recipient C57BL/6 mice was examined by FCM (flow cytometer)from 1 to 8 weeks after skin transplant(n=6).
Results(1)Heterologous series of skin transplant group:Compared with the number of memory T cells from 1-3th week,there was a significant increase from 4th week after operation(P＜0.01);as well as in 5-8th week compared with the 4th week after operation(P＜0.01);There was no significant increase in the number of memory T cells in 1-3th(P＞0.05)week after operation as well as in 5-8th week(P＞0.05).(2) Homologous series of skin transplant group:There was no significant increase in the number of memory T cells in 1-8 th week after operation(P＞0.05).
Conclusion Memory T cells of mice have its homeostasis proliferation during the exposure to skin allogenic antigen in 4-5 weeks.This model has a stable increased state of memory T cells in mice which could be useful for transplant study.
PART TWO Effects ofrapamycin on mouse memory T cells in vitro
Objective To investigate the effects of rapamycin on proliferation and levels of interleukin-2(IL-2)of mouse memory T cells in vitro.The sensitive difference to rapamycin was compared in naive T cells and memory T cells of mice mouse naive T cells,and investigate a mechanism of rapamycin on mouse memory T cells.
Methods Harvest mononuclearcell from C57BL/6 mouse's spleen,and then separate memory T cells by Magnetic Cell Sorting System.Harvest mononuclearcell from C57BL/6 mouse's spleen,which memory T cells have been induced by frontal experiment.Separate memory T cells by fluorescence-activated cell sorting(FACS).Various concentrations of repamycin(0 ng/ml、10 ng/ml、20 ng/ml、30 ng/ml)were used to culture the memory T cells for 72 hours,the activity of cells and levels of IL-2 were measured by MTT(methylthiazlyltetrazolium)assay and Elisa.At the same time,we detected memory T cells' cell cycle by Flow cytometer cultured with 10ng/ml repamycin stimulation.Finally,the expression of IL-2 receptor(α、β、γsubset)mRNAwas detected by RT-PCR.
Results Proliferation of naive and memory T cells and expression of IL-2 were suppressed by rapamycin medium when cultured with rapamycin(P＜0.01).This suppression effect is in a dose-dependent manner(P＜0.01).And at the same concentrations of repamycin, memory T cells are less suppressed compared with naive T cells. (P＜0.01).The cell population increseased in the G_0G_1 phase (P＜0.01)and decreased in the S phase(P＜0.01).The expression of the IL-2R(α、β、γsubset)mRNA were significantly reduced in experimental group.
Conclusion In vitro,rapamycin is a potential inhibitor that blocks the proliferation and the expression of IL-2 of both naive and memory T cells,memory T cells are less suppressed compared with naive T cells.Rapamycin inhibit proliferation of memory T cells by blocks the expression of IL-2,IL-2R(α、β、γsubset)mRNA and cell cycle.
目的:建立一种稳定的通过小鼠皮肤移植获得小鼠记忆T细胞的方法,为研究药物对小鼠记忆T细胞的体外作用做准备。
方法:以C57BL/6小鼠为受者、DBA╱2小鼠为供者行皮肤移植;同时行C57BL/6小鼠行同种同系皮肤移植做对照。术后1-8周,每周取小鼠脾脏,使用流式细胞仪检测所有受体鼠脾单个核细胞悬液中记忆T细胞的比例(n=6)。
结果:(1)同种异系皮肤移植组:术后第4周的C57BL/6小鼠脾单个核细胞悬液中记忆T细胞的比例较术后1-3周显著增多(P＜0.01);术后5-8周的记忆T细胞比例较术后第4周显著增多(P＜0.01);术后1-3周小鼠记忆T细胞比例无差异(P＞0.05);术后5-8周小鼠记忆T细胞比例无差异(P＞0.05)。(2)同种同系皮肤移植组:术后8周,每周产生的记忆T细胞比例无差异(P＞0.05)。
结论:接受同种异系皮肤抗原刺激4-5周后,小鼠记忆T细胞发生稳态增殖,此模型可以稳定的获得小鼠记忆T细胞。
第二部分雷帕霉素对小鼠记忆T细胞的体外作用
目的:探讨雷帕霉素对小鼠记忆T细胞的体外生长及白介素-2(IL-2)表达的影响,比较其与初始T细胞对雷帕霉素的敏感性差异,并且初步探讨雷帕霉素对小鼠记忆T细胞抑制作用的机制。
方法:取6周龄以下的C57BL/6小鼠脾脏制备成脾单个核细胞,使用免疫磁珠法分选出小鼠初始T淋巴细胞;取第一部分实验中经过同种异系皮肤移植存活6周以上的C57BL/6小鼠,荧光激活细胞分类术(FACS fluorescence-activated cell sorting)分选出小鼠记忆T细胞。将分选出的小鼠初始和记忆T细胞分别加入0ng/ml、10ng/ml、20ng/ml、30ng/ml梯度浓度的雷帕霉素培养液培养72h后,采用MTT法及Elisa法测定各组细胞的生长情况及IL-2表达情况。同样于72小时后测定10ng/ml雷帕霉素浓度组及对照组(0ng/ml)小鼠记忆T细胞细胞周期的变化,并且使用RT-PCR检测其IL-2R(α、β、γ亚基)mRNA表达情况。
结果:用雷帕霉素培养液培养细胞时,小鼠初始和记忆T细胞生长及IL-2的表达均受到抑制(P＜0.01);随药物浓度增加,细胞生长及IL-2表达受抑制越明显(P＜0.01);同浓度雷帕霉素对于记忆T细胞的生长及IL-2的表达的抑制程度均较初始T细胞弱(P＜0.01);细胞周期检测结果示,实验组与对照组相比,G_0G_1期细胞的比例升高(P＜0.01),S期降低(P＜0.01)。RT-PCR结果显示实验组与对照组IL-2R(α、β、γ亚基)mRNA的表达均有显著性差异(P＜0.01)。
结论:在体外雷帕霉素对小鼠初始和记忆T细胞的生长、IL-2的表达起抑制作用,且随浓度增加,抑制作用增强;且雷帕霉素对小鼠记忆T细胞的抑制作用程度较初始T细胞弱。雷帕霉素通过抑制小鼠记忆T细胞的IL-2R(α、β、γ亚基)及IL-2的表达,并且阻滞其细胞周期来抑制其生长。
Effects of rapamycin on mouse memory T cells in vitro
PART ONE Proliferation of memory T cells in mice by rejection after skin transplant model
Objective To harvest a stable proliferation of memory T cells by T cell proliferation in C57BL/6 mice with skin transplant model.To prepare for the drug effect on the cell in vitro.
Methods We transplanted DBA/2 donors'skin to C57BL/6 recipients. At the same time,transplanted C57BL/6 donors'skin to C57BL/6 hosts as control.The proportion of memory T cells in SPM(spleen mononuclearcell)from recipient C57BL/6 mice was examined by FCM (flow cytometer)from 1 to 8 weeks after skin transplant(n=6).
Results(1)Heterologous series of skin transplant group:Compared with the number of memory T cells from 1-3th week,there was a significant increase from 4th week after operation(P＜0.01);as well as in 5-8th week compared with the 4th week after operation(P＜0.01);There was no significant increase in the number of memory T cells in 1-3th(P＞0.05)week after operation as well as in 5-8th week(P＞0.05).(2) Homologous series of skin transplant group:There was no significant increase in the number of memory T cells in 1-8 th week after operation(P＞0.05).
Conclusion Memory T cells of mice have its homeostasis proliferation during the exposure to skin allogenic antigen in 4-5 weeks.This model has a stable increased state of memory T cells in mice which could be useful for transplant study.
PART TWO Effects ofrapamycin on mouse memory T cells in vitro
Objective To investigate the effects of rapamycin on proliferation and levels of interleukin-2(IL-2)of mouse memory T cells in vitro.The sensitive difference to rapamycin was compared in naive T cells and memory T cells of mice mouse naive T cells,and investigate a mechanism of rapamycin on mouse memory T cells.
Methods Harvest mononuclearcell from C57BL/6 mouse's spleen,and then separate memory T cells by Magnetic Cell Sorting System.Harvest mononuclearcell from C57BL/6 mouse's spleen,which memory T cells have been induced by frontal experiment.Separate memory T cells by fluorescence-activated cell sorting(FACS).Various concentrations of repamycin(0 ng/ml、10 ng/ml、20 ng/ml、30 ng/ml)were used to culture the memory T cells for 72 hours,the activity of cells and levels of IL-2 were measured by MTT(methylthiazlyltetrazolium)assay and Elisa.At the same time,we detected memory T cells' cell cycle by Flow cytometer cultured with 10ng/ml repamycin stimulation.Finally,the expression of IL-2 receptor(α、β、γsubset)mRNAwas detected by RT-PCR.
Results Proliferation of naive and memory T cells and expression of IL-2 were suppressed by rapamycin medium when cultured with rapamycin(P＜0.01).This suppression effect is in a dose-dependent manner(P＜0.01).And at the same concentrations of repamycin, memory T cells are less suppressed compared with naive T cells. (P＜0.01).The cell population increseased in the G_0G_1 phase (P＜0.01)and decreased in the S phase(P＜0.01).The expression of the IL-2R(α、β、γsubset)mRNA were significantly reduced in experimental group.
Conclusion In vitro,rapamycin is a potential inhibitor that blocks the proliferation and the expression of IL-2 of both naive and memory T cells,memory T cells are less suppressed compared with naive T cells.Rapamycin inhibit proliferation of memory T cells by blocks the expression of IL-2,IL-2R(α、β、γsubset)mRNA and cell cycle.
引文
1 Lechler RI,Sykes M,Thomson AW, et al.Organ transplantation how much of the promise has been realized?Nature Medicine,2005,11 (6):605-613.
2 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
3 Kedl RM, Mescher MF. Qualitative differences between naive and memory T cells make a major contribution to the more rapid and efficient memory CD8+T cell response. J Immunol 1998; 161: 674-683.
4 Cho BK, Wang C, Sugawa S, et al. Functional differences between memory and naive CD8 T cells. Proc Natl Acad Sci U S A 1999; 96: 2976-2981.
5 London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
6 Heeger PS, Valujskikh A, Lehmann PV. Comprehensive assessment of determinant specificity, frequency, and cytokine signature of the primed CD8 cell repertoire induced by a minor trans-plantation antigen. J Immunol 2000; 165: 1278-1284.
7 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002,2 0:551-579.
8 Monk NJ, Hargreaves RE, Simpson E,et al.Transplant tolerance:
models, concepts and facts.J Mol Med,2006,84(4):295-304.
1 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
2 Anna Valujski,Xian Chang Li.Frontiers in Nephrology:T Cell Memory as a Barrier to Transplant Tolerance[J]. J Am Soc Nephrol ,2007,18(8):2252-2261.
3 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002,20:551-579.
4 Monk NJ, Hargreaves RE, Simpson E,et al.Transplant tolerance: models, concepts and facts.J Mol Med,2006,84(4):295-304.
5 Susan L. Swain, Javed N. Agrewala, Deborah M. Brown, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza[J].Immunological Reviews,2006,211:8-22.
6 Lefrancois.Development, trafficking, and function of memory T cell subsets[J]. Immunological Reviews,2006 ,211:93-103.
7 Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific,IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes[J].J Immunol,1999,163(4):2267-2275.
8 Farber DL,Ahmadzadeh M.Dissecting the complexity of the me mory Y cell response[J].Immunol Res,2002,25(3):247-259.
9 Hikono H,Kohlmeier JE,Ely KH,et al.T-cell memory and reca -ll responses to respiratory virus infections[J].Immunol Rev,2006,211:119-132.
10 Ndejembi MP,Teijaro JR,Patke DS,et al.Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway[J].J Immunol,2006,177(11):7698-7706.
11 刘振红,张长品,张勇,等.简便的小鼠皮片移植方法[J].首都医科大学学报,2003,24(2):204-205.
1 胡新华,杨军,刘程伟,等.mTOR信号转导通路在自体移植静脉中的表达及意义[J].中华普通外科杂志,2006,21(12):889-892.
2 陈宏林,尤庆生,沈卫东,等.雷帕霉素抑制兔自体移植静脉内膜过度增殖[J].江苏医药,2007,33(5):500-502.
3 周建军,乐秀芳,韩家娴,等.评价抗癌物质活性的改良MTT方法[J].中国医药工业杂志,1993,24(10):455-457.
4 Jones ND, Carvalho-Gaspar M, Luo S,et al.Effector and Memory CD8+T Cells Can Be Generated in Response to Alloantigen Independently of CD4+T Cell Help [J].The Journal of Immunology,2006, 176(4): 2316-2323.
5 Chen M, Li XC.Approaches and challenges in targeting memory T cells in transplant tolerance.Arch Immunol Ther Exp (Warsz),2007, 55(5):309-314.
6 Valujskikh A, Li XC.Frontiers in nephrology: T cell memory as a barrier to transplant tolerance.J Am Soc Nephrol,2007,18(8):2252-22 61.
7 Gregori S, Bacchetta R, Passerini L, et al.Isolation, expansion, and characterization of human natural and adaptive regulatory T cells. Methods Mol Biol,2007,380:83-105.
8 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
9 Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen: memory cells are less dependent on accessory cell costimulation and can respond to many APC types including resting B cells. J Immunol 1994; 152: 2675-2685.
10 Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+T cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000; 164:5146-5155.
11 London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
12 Kreuwel HT, Aung S, Silao C, et al. Memory CD8 (+) T cells undergo peripheral tolerance. Immunity 2002; 17: 73-81.
13 Kroemer A, Xiao X,Li XC, et al.OX40 controls functionally diff erent T cell subsets and their resistance to depletion therapy.J Immunol,2007,179(8):5584-91.
14 Vu MD, Amanullah F,Li XC,et al.Different costimulatory and growth factor requirements for CD4+ and CD8+ T cell-mediated rejection. J Immunol,2004,173(1):214-221.
15 Vu MD, Clarkson MR,Li XC, et al.Critical, but conditional, role of OX40 in memory T cell-mediated rejection.J Immunol,2006,176 (3):1394-1401.
16 Demirci G,Amanullah F,Li XC, et al.Critical role of OX40 in C D28 and CD154-independent rejection.J Immunol. 2004,172(3): 1691-1698.
17 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002, 20:551-579.
18 Kato M, Watarai S, Nishikawa S,,et.al.A Novel Culture Method of Canine Peripheral Blood Lymphocytes with Concanavalin A and Recombinant Human Interleukin-2 for Adoptive Immunotherapy[J].J Vet Med Sci,2007,69(5):481-486.
19 Hiroshi ITOH,Tomoko KAKUTA,Tetsuya KUDO,et al.Bulk Cult ures of Canine Peripheral Blood Lymphocytes with Solid Phase Ant i-CD3 Antibody and Recombinant Interleukin-2 for Use in Immunot herapy[J].J Vet Med Sci,2003,65(3):329-333.
20 Masahiro KATO,Shinobu WATARAI,Shigeru NISHIKAWA,et al.A Novel Culture Method of Canine Peripheral Blood Lymphocytes withConcanavalin A and Recombinant Human Interleukin-2 for Ado ptive Immunotherapy[J].Immunology,2007,2:481-486.
21 Emeson,E.E.,Norin,A.J.et al.Lectindependent cell-mediated cytotoxicity.A new and simple method to quantitate cytotoxic T cell activity in dogs[J].Transplantation,1982,33:365-369.
22 Dickerson,E.B.,Fosmire,S.,Padilla,M.L.,et al.Potential to t arget dysregulated interleukin-2 receptor expression in canine lymph oid and hematopoietic malignancies as a model for human cancer.J.Immunother,2002,25:36-45
23 张莹,姚永明,常青,等.不同刺激剂对小鼠调节性T细胞功能活化的影响[J].中国危重病急救医学,2007,19(3):142-145.
24 Leonard A.Herzenberg,David Parks,Bita Sahaf,et al.The History and Future of the Fluorescence Activated Cell Sorter and Flow Cytometry:A View fromStanford[J].Clinical Chemistry,2002,48(10):1819- 1827.
25 Lauren Nico.laisenFluorescence-Activated Cell Sorting in Microfl uidic Devices[M],University of Colorado.
26 陶家平,马仕良.FACSVantageSE流式细胞仪特点和应用[J].现代仪器,2000,2:29-30
27 施家琦,唐冬生,夏家辉,等.双参数人类染色体流式分析及分选[J].激光生物学报,1998,7(1):21-23.
28 Dong-Gyun Lim,In-Yi Joe,Youn-Hee Park,et al.Effect of immu nosuppressants on the expansion and function of naturally occurring regulatory T cells[J].Transplant Immunology,18(2007)94-100.
1. Cerny A, Ramseier H, Bazin H, et al. Unimpaired first-set and second-set skin graft rejection in agammaglobulinemic mice. Transplantation 1988; 45: 1111-3.
2. Hall BM, Dorsch S, Roser B. The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection. J Exp Med 1978; 148: 890-902.
3. Heeger PS, Greenspan NS, Kuhlenschmidt S et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999; 163: 2267-2275.
4. Sallusto F, Lenig D, Forster R, et al. Two sub-sets of memory T lymphocytes with distinct homing potentials and effector functions [see comments]. Nature 1999; 401: 708-712.
5. Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291:2413-2417.
6. Farber DL, Commentary. Differential TCR signaling and the generation of memory T cells. J Immunol 1998; 160: 535-539.
7. Wang XN, Proctor SJ, Dickinson AM. Frequency analysis of recipient-reactive helper and cytotoxic T lymphocyte precursors using a combined single limiting dilution assay. Transpl Immunol 1996; 4: 247-251.
8. Ford WL, Atkins RC. The proportion of lymphocytes capable of recognizing strong transplantation antigens in vivo. Adv Exp Med Biol 1973; 29: 255-262.
9. Deacock SJ, Lechler RI. Positive correlation of T cell sensitization with frequencies of alloreactive T helper cells in chronic renal failure patients. Transplantation 1992; 54: 338-343.
10. Merkenschlager M, Terry L, Edwards, et al. Limiting dilution analysis of proliferative responses in human lymphocyte populations defined by the monoclonal antibody UCHL1: implications for differential CD45 expression in T cell memory formation.Eur J Immunol 1988; 18: 1653-1661.
11. Lombardi G, Sidhu S, Daly M, et al. Are primary alloresponses truly primary? Int Immunol 1990;2: 9-13.
12. Brehm MA, Markees TG, Daniels KA, et al. Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infections. J Immunol 2003; 170: 4077-4086.
13. Pantenburg B, Heinzel F, Das L, et al. T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 2002; 169: 3686-3693.
14. Adams AB, Williams MA, Jones TR et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111: 1887-1895.
15. Burrows SR, Khanna R, Burrows JM, et al. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease. J Exp Med 1994; 179: 1155-1161.
16. Burrows SR, Silins SL, Khanna R et al. Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major his-tocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur J Immunol 1997; 27: 1726-1736.
17. Lombardi G, Sidhu S, Lamb JR, et al. Corecognition of endogenous antigens with HLA-DRl by alloreactive human T cell clones. J Immunol 1989; 142: 753-759.
18. Lee WT, Vitetta ES. Limiting dilution analysis of CD45Rhiand CD45RloT cells: further evidence that CD45Rlocells are memory cells. Cell Immunol 1990; 130: 459-471.
19. Murali-Krishna K, Altman JD, Suresh M et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998; 8: 177-187.
20. DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997; 278: 672-675.
21. Akbar AN, Terry L, Timrns A, et al. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 1988; 140: 2171-2178.
22. Bottomly K, Luqman M, Greenbaum L et al. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur J Immunol 1989; 19: 617-623.
23. Ahmadzadeh M, Hussain SF, Farber DL. Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells. J Immunol 2001; 166: 926-935.
24. Bradley LM, Watson SR, Swain SL. Entry of naive CD4 T cells into peripheral lymph nodes requires L-selectin. J Exp Med 1994; 180: 2401-2406.
25. Wherry EJ, Teichgraber V, Becker TC et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003; 4: 225-234.
26. Champagne P, Ogg GS, King AS et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001; 410: 106-111.
27. Kivisakk P, Mahad DJ, Callahan MK et al. Human cerebrospinal fluid central memory CD4+T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 2003; 100: 8389-8394.
28. Chalasani G, Dai Z, Konieczny BT, et al. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A 2002; 99:6175-6180.
29. Kedl RM, Mescher MF. Qualitative differences between naive and memory T cells make a major contribution to the more rapid and efficient memory CD8+T cell response. J Immunol 1998;161: 674-683.
30. Cho BK, Wang C, Sugawa S, et al. Functional differences between memory and naive CD8 T cells. Proc Natl Acad Sci U S A 1999; 96: 2976-2981.
31. Ahmadzadeh M, Hussain SF, Farber DL. Effector CD4 T cells are biochemically distinct from the memory subset: evidence for long-term persistence of effectors in vivo. J Immunol 1999; 163:3053-3063.
32. Rogers PR, Dubey C, Swain SL. Qualitative changes accompany memory T cell generation. faster, more effective responses at lower doses of antigen. J Immunol 2000; 164: 2338-2346.
33. Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen: memory cells are less dependent on accessory cell costimulation and can respond to many APC types including resting B cells. J Immunol 1994; 152: 2675-2685.
34. Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+T cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000; 164:5146-5155.
35. Hancock WW, Gao W, Shemmeri N et al. Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms. Transplantation 2002; 73: 1392-1397.
36. Cecka JM. Living donor transplants. Clin Transpl 1995: 363-377.
37. Kobashigawa JA, Sabad A, Drinkwater D et al. Pretransplant panel reactive-antibody screens. Are they truly a marker for poor outcome after cardiac transplantation? Circulation 1996; 94: 294-297.
38. Kupiec-Weglinski JW. Graft rejection in sensitized recipients. Ann Transplant 1996; 1: 34-40.
39. Heeger PS, Valujskikh A, Lehmann PV. Comprehensive assessment of determinant specificity, frequency, and cytokine signature of the primed CD8 cell repertoire induced by a minor trans-plantation antigen. J Immunol 2000; 165: 1278-1284.
40. Kersh EN, Kaech SM, Onami TM et al. TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells. J Immunol 2003; 170: 5455-5463.
41. Krishnan S, Warke VG, Nambiar MP, et al. Generation and biochemical analysis of human effector CD4 T cells. alterations in tyrosine phosphorylation and loss of CD3f expression. Blood 2001; 97: 3851-3859.
42. Hussain SF, Anderson CF, Farber DL. Differential SLP-76Expression and TCR-Mediated Signaling in Effector and Memory CD4 T Cells. J Immunol 2002; 168: 1557-1565.
43. Robinson AT, Miller N, Alexander DR. CD3 antigen-mediated calcium signals and protein kinase C activation are higher in CD45RO+than in CD45RA+human T lymphocyte subsets. Eur J Immunol 1993; 23: 61-68.
44. Gupta M, Satyaraj E, Durdik JM, et al. Differential regulation of T cell activation for primary versus secondary proliferative responses. J Immunol 1997; 158: 4113-4121.
45. Dai Z, Konieczny BT, Lakkis FG. The dual role of IL-2 in the generation and maintenance of CD8+memory T cells. J Immunol 2000; 165: 3031-3036.
46. Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003; 3: 269-279.
47. Goldrath AW, Sivakumar PV, Glaccum M et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+T cells. J Exp Med 2002; 195: 1515-1522.
48. Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 2002; 168: 4827-4831.
49. Becker TC, Wherry EJ, Boone D et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 2002; 195: 1541-1548.
50. Kondrack RM, Harbertson J, Tan JT, et al. Interleukin 7 regulates the survival and generation of memory CD4 cells. J Exp Med 2003; 198: 1797-1806.
51. Li J, Huston G, Swain SL. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J Exp Med 2003; 198: 1807-1815.
52. Hancock WW, Wang L, YeQ,et al. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol 2003; 15: 479-486.
53. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998; 338: 1813-1821.
54. Larsen CP, Elwood ET, Alexander DZ et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381: 434-438.
55. Valujskikh A, Pantenburg B, Heeger PS. Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant 2002; 2: 501-509.
56. Williams MA, Onami TM, Adams AB et al. Cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following CD28/CD40 blockade-based regimen. J Immunol 2002; 169: 5387-5391.
57. Welsh RM, Markees TG, Woda BA et al. Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J Virol 2000; 74: 2210-2218.
58. London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
59. Sachs DH, Tolerance. of mice and men. J Clin Invest 2003; 111: 1819-1821.
60. Makhlouf L, Kishimoto K, Smith RN et al. The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade. Diabetes 2002; 51: 3202-3210.
61. Okitsu T, Bartlett ST, Hadley GA, et al. Recurrent autoimmunity accelerates destruction of minor and major histoincompatible islet grafts in nonobese diabetic (NOD) mice.Am J Transplant 2001; 1: 138-145.
62. Cooke A, Phillips JM, Parish NM. Tolerogenic strategies to halt or prevent type 1 diabetes. Nat Immunol 2001; 2: 810-815.
63. Kreuwel HT, Aung S, Silao C, et al. Memory CD8 (+) T cells undergo peripheral tolerance. Immunity 2002; 17: 73-81.
64. Mirshahidi S, Huang CT, Sadegh-Nasseri S. Anergy in peripheral memory CD4 (+) T cells induced by low avidity engagement of T cell receptor. J Exp Med 2001; 194: 719-731.
65. Ahmadzadeh M, Farber DL. Functional plasticity of an antigen-specific memory CD4 T cell population. Proc Natl Acad Sci U S A 2002; 99: 11802-11807.
66. Dai Z, Li Q, Wang Y, et al. CD4+CD25+regulatory T cells suppress allograft rejection mediated by memory CD8+T cells via a CD30-dependent mechanism. J Clin Invest 2004; 113:310-317.
67. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003; 3: 609-620.
68. Yuan X, Salama AD, Dong V et al. The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo. J Immunol 2003; 170: 2949-2955.
69. Khayyamian S, Hutloff A, Buchner K et al. ICOS-ligand, expressed on human endothelial cells, costimulates Thl and Th2 cytokine secretion by memory CD4+T cells. Proc Natl Acad Sci U S A 2002; 99: 6198-6203.
70. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345: 248-255.
71. Dedrick RL, Walicke P, Garovoy M. Anti-adhesion antibodies Efal-izumab, a humanized anti-CDl la monoclonal antibody. Trans Immunol 2002; 9: 181-186.
72. Demirci G, Strom TB, Li XC. Islet allograft rejection in nonobese diabetic mice involves the common gamma-chain and CD28/CD 154-dependent and -independent mechanisms.J Immunol 2003;171:3878-3885.
2 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
3 Kedl RM, Mescher MF. Qualitative differences between naive and memory T cells make a major contribution to the more rapid and efficient memory CD8+T cell response. J Immunol 1998; 161: 674-683.
4 Cho BK, Wang C, Sugawa S, et al. Functional differences between memory and naive CD8 T cells. Proc Natl Acad Sci U S A 1999; 96: 2976-2981.
5 London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
6 Heeger PS, Valujskikh A, Lehmann PV. Comprehensive assessment of determinant specificity, frequency, and cytokine signature of the primed CD8 cell repertoire induced by a minor trans-plantation antigen. J Immunol 2000; 165: 1278-1284.
7 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002,2 0:551-579.
8 Monk NJ, Hargreaves RE, Simpson E,et al.Transplant tolerance:
models, concepts and facts.J Mol Med,2006,84(4):295-304.
1 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
2 Anna Valujski,Xian Chang Li.Frontiers in Nephrology:T Cell Memory as a Barrier to Transplant Tolerance[J]. J Am Soc Nephrol ,2007,18(8):2252-2261.
3 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002,20:551-579.
4 Monk NJ, Hargreaves RE, Simpson E,et al.Transplant tolerance: models, concepts and facts.J Mol Med,2006,84(4):295-304.
5 Susan L. Swain, Javed N. Agrewala, Deborah M. Brown, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza[J].Immunological Reviews,2006,211:8-22.
6 Lefrancois.Development, trafficking, and function of memory T cell subsets[J]. Immunological Reviews,2006 ,211:93-103.
7 Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor-specific,IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes[J].J Immunol,1999,163(4):2267-2275.
8 Farber DL,Ahmadzadeh M.Dissecting the complexity of the me mory Y cell response[J].Immunol Res,2002,25(3):247-259.
9 Hikono H,Kohlmeier JE,Ely KH,et al.T-cell memory and reca -ll responses to respiratory virus infections[J].Immunol Rev,2006,211:119-132.
10 Ndejembi MP,Teijaro JR,Patke DS,et al.Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway[J].J Immunol,2006,177(11):7698-7706.
11 刘振红,张长品,张勇,等.简便的小鼠皮片移植方法[J].首都医科大学学报,2003,24(2):204-205.
1 胡新华,杨军,刘程伟,等.mTOR信号转导通路在自体移植静脉中的表达及意义[J].中华普通外科杂志,2006,21(12):889-892.
2 陈宏林,尤庆生,沈卫东,等.雷帕霉素抑制兔自体移植静脉内膜过度增殖[J].江苏医药,2007,33(5):500-502.
3 周建军,乐秀芳,韩家娴,等.评价抗癌物质活性的改良MTT方法[J].中国医药工业杂志,1993,24(10):455-457.
4 Jones ND, Carvalho-Gaspar M, Luo S,et al.Effector and Memory CD8+T Cells Can Be Generated in Response to Alloantigen Independently of CD4+T Cell Help [J].The Journal of Immunology,2006, 176(4): 2316-2323.
5 Chen M, Li XC.Approaches and challenges in targeting memory T cells in transplant tolerance.Arch Immunol Ther Exp (Warsz),2007, 55(5):309-314.
6 Valujskikh A, Li XC.Frontiers in nephrology: T cell memory as a barrier to transplant tolerance.J Am Soc Nephrol,2007,18(8):2252-22 61.
7 Gregori S, Bacchetta R, Passerini L, et al.Isolation, expansion, and characterization of human natural and adaptive regulatory T cells. Methods Mol Biol,2007,380:83-105.
8 Bingaman AW,Farber DL.Memory T Cells in Transplantation: Generation ,Function, and Potential Role in Rejection [J].American Journal of Transplantation,2004,4(6): 846-852.
9 Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen: memory cells are less dependent on accessory cell costimulation and can respond to many APC types including resting B cells. J Immunol 1994; 152: 2675-2685.
10 Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+T cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000; 164:5146-5155.
11 London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
12 Kreuwel HT, Aung S, Silao C, et al. Memory CD8 (+) T cells undergo peripheral tolerance. Immunity 2002; 17: 73-81.
13 Kroemer A, Xiao X,Li XC, et al.OX40 controls functionally diff erent T cell subsets and their resistance to depletion therapy.J Immunol,2007,179(8):5584-91.
14 Vu MD, Amanullah F,Li XC,et al.Different costimulatory and growth factor requirements for CD4+ and CD8+ T cell-mediated rejection. J Immunol,2004,173(1):214-221.
15 Vu MD, Clarkson MR,Li XC, et al.Critical, but conditional, role of OX40 in memory T cell-mediated rejection.J Immunol,2006,176 (3):1394-1401.
16 Demirci G,Amanullah F,Li XC, et al.Critical role of OX40 in C D28 and CD154-independent rejection.J Immunol. 2004,172(3): 1691-1698.
17 Sprent J, Surh CD. T cell memory[J]. Annu Rev Immunol,2002, 20:551-579.
18 Kato M, Watarai S, Nishikawa S,,et.al.A Novel Culture Method of Canine Peripheral Blood Lymphocytes with Concanavalin A and Recombinant Human Interleukin-2 for Adoptive Immunotherapy[J].J Vet Med Sci,2007,69(5):481-486.
19 Hiroshi ITOH,Tomoko KAKUTA,Tetsuya KUDO,et al.Bulk Cult ures of Canine Peripheral Blood Lymphocytes with Solid Phase Ant i-CD3 Antibody and Recombinant Interleukin-2 for Use in Immunot herapy[J].J Vet Med Sci,2003,65(3):329-333.
20 Masahiro KATO,Shinobu WATARAI,Shigeru NISHIKAWA,et al.A Novel Culture Method of Canine Peripheral Blood Lymphocytes withConcanavalin A and Recombinant Human Interleukin-2 for Ado ptive Immunotherapy[J].Immunology,2007,2:481-486.
21 Emeson,E.E.,Norin,A.J.et al.Lectindependent cell-mediated cytotoxicity.A new and simple method to quantitate cytotoxic T cell activity in dogs[J].Transplantation,1982,33:365-369.
22 Dickerson,E.B.,Fosmire,S.,Padilla,M.L.,et al.Potential to t arget dysregulated interleukin-2 receptor expression in canine lymph oid and hematopoietic malignancies as a model for human cancer.J.Immunother,2002,25:36-45
23 张莹,姚永明,常青,等.不同刺激剂对小鼠调节性T细胞功能活化的影响[J].中国危重病急救医学,2007,19(3):142-145.
24 Leonard A.Herzenberg,David Parks,Bita Sahaf,et al.The History and Future of the Fluorescence Activated Cell Sorter and Flow Cytometry:A View fromStanford[J].Clinical Chemistry,2002,48(10):1819- 1827.
25 Lauren Nico.laisenFluorescence-Activated Cell Sorting in Microfl uidic Devices[M],University of Colorado.
26 陶家平,马仕良.FACSVantageSE流式细胞仪特点和应用[J].现代仪器,2000,2:29-30
27 施家琦,唐冬生,夏家辉,等.双参数人类染色体流式分析及分选[J].激光生物学报,1998,7(1):21-23.
28 Dong-Gyun Lim,In-Yi Joe,Youn-Hee Park,et al.Effect of immu nosuppressants on the expansion and function of naturally occurring regulatory T cells[J].Transplant Immunology,18(2007)94-100.
1. Cerny A, Ramseier H, Bazin H, et al. Unimpaired first-set and second-set skin graft rejection in agammaglobulinemic mice. Transplantation 1988; 45: 1111-3.
2. Hall BM, Dorsch S, Roser B. The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection. J Exp Med 1978; 148: 890-902.
3. Heeger PS, Greenspan NS, Kuhlenschmidt S et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999; 163: 2267-2275.
4. Sallusto F, Lenig D, Forster R, et al. Two sub-sets of memory T lymphocytes with distinct homing potentials and effector functions [see comments]. Nature 1999; 401: 708-712.
5. Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291:2413-2417.
6. Farber DL, Commentary. Differential TCR signaling and the generation of memory T cells. J Immunol 1998; 160: 535-539.
7. Wang XN, Proctor SJ, Dickinson AM. Frequency analysis of recipient-reactive helper and cytotoxic T lymphocyte precursors using a combined single limiting dilution assay. Transpl Immunol 1996; 4: 247-251.
8. Ford WL, Atkins RC. The proportion of lymphocytes capable of recognizing strong transplantation antigens in vivo. Adv Exp Med Biol 1973; 29: 255-262.
9. Deacock SJ, Lechler RI. Positive correlation of T cell sensitization with frequencies of alloreactive T helper cells in chronic renal failure patients. Transplantation 1992; 54: 338-343.
10. Merkenschlager M, Terry L, Edwards, et al. Limiting dilution analysis of proliferative responses in human lymphocyte populations defined by the monoclonal antibody UCHL1: implications for differential CD45 expression in T cell memory formation.Eur J Immunol 1988; 18: 1653-1661.
11. Lombardi G, Sidhu S, Daly M, et al. Are primary alloresponses truly primary? Int Immunol 1990;2: 9-13.
12. Brehm MA, Markees TG, Daniels KA, et al. Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infections. J Immunol 2003; 170: 4077-4086.
13. Pantenburg B, Heinzel F, Das L, et al. T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 2002; 169: 3686-3693.
14. Adams AB, Williams MA, Jones TR et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111: 1887-1895.
15. Burrows SR, Khanna R, Burrows JM, et al. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease. J Exp Med 1994; 179: 1155-1161.
16. Burrows SR, Silins SL, Khanna R et al. Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major his-tocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur J Immunol 1997; 27: 1726-1736.
17. Lombardi G, Sidhu S, Lamb JR, et al. Corecognition of endogenous antigens with HLA-DRl by alloreactive human T cell clones. J Immunol 1989; 142: 753-759.
18. Lee WT, Vitetta ES. Limiting dilution analysis of CD45Rhiand CD45RloT cells: further evidence that CD45Rlocells are memory cells. Cell Immunol 1990; 130: 459-471.
19. Murali-Krishna K, Altman JD, Suresh M et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998; 8: 177-187.
20. DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 1997; 278: 672-675.
21. Akbar AN, Terry L, Timrns A, et al. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 1988; 140: 2171-2178.
22. Bottomly K, Luqman M, Greenbaum L et al. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur J Immunol 1989; 19: 617-623.
23. Ahmadzadeh M, Hussain SF, Farber DL. Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells. J Immunol 2001; 166: 926-935.
24. Bradley LM, Watson SR, Swain SL. Entry of naive CD4 T cells into peripheral lymph nodes requires L-selectin. J Exp Med 1994; 180: 2401-2406.
25. Wherry EJ, Teichgraber V, Becker TC et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003; 4: 225-234.
26. Champagne P, Ogg GS, King AS et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001; 410: 106-111.
27. Kivisakk P, Mahad DJ, Callahan MK et al. Human cerebrospinal fluid central memory CD4+T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 2003; 100: 8389-8394.
28. Chalasani G, Dai Z, Konieczny BT, et al. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A 2002; 99:6175-6180.
29. Kedl RM, Mescher MF. Qualitative differences between naive and memory T cells make a major contribution to the more rapid and efficient memory CD8+T cell response. J Immunol 1998;161: 674-683.
30. Cho BK, Wang C, Sugawa S, et al. Functional differences between memory and naive CD8 T cells. Proc Natl Acad Sci U S A 1999; 96: 2976-2981.
31. Ahmadzadeh M, Hussain SF, Farber DL. Effector CD4 T cells are biochemically distinct from the memory subset: evidence for long-term persistence of effectors in vivo. J Immunol 1999; 163:3053-3063.
32. Rogers PR, Dubey C, Swain SL. Qualitative changes accompany memory T cell generation. faster, more effective responses at lower doses of antigen. J Immunol 2000; 164: 2338-2346.
33. Croft M, Bradley LM, Swain SL. Naive versus memory CD4 T cell response to antigen: memory cells are less dependent on accessory cell costimulation and can respond to many APC types including resting B cells. J Immunol 1994; 152: 2675-2685.
34. Dengler TJ, Pober JS. Human vascular endothelial cells stimulate memory but not naive CD8+T cells to differentiate into CTL retaining an early activation phenotype. J Immunol 2000; 164:5146-5155.
35. Hancock WW, Gao W, Shemmeri N et al. Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms. Transplantation 2002; 73: 1392-1397.
36. Cecka JM. Living donor transplants. Clin Transpl 1995: 363-377.
37. Kobashigawa JA, Sabad A, Drinkwater D et al. Pretransplant panel reactive-antibody screens. Are they truly a marker for poor outcome after cardiac transplantation? Circulation 1996; 94: 294-297.
38. Kupiec-Weglinski JW. Graft rejection in sensitized recipients. Ann Transplant 1996; 1: 34-40.
39. Heeger PS, Valujskikh A, Lehmann PV. Comprehensive assessment of determinant specificity, frequency, and cytokine signature of the primed CD8 cell repertoire induced by a minor trans-plantation antigen. J Immunol 2000; 165: 1278-1284.
40. Kersh EN, Kaech SM, Onami TM et al. TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells. J Immunol 2003; 170: 5455-5463.
41. Krishnan S, Warke VG, Nambiar MP, et al. Generation and biochemical analysis of human effector CD4 T cells. alterations in tyrosine phosphorylation and loss of CD3f expression. Blood 2001; 97: 3851-3859.
42. Hussain SF, Anderson CF, Farber DL. Differential SLP-76Expression and TCR-Mediated Signaling in Effector and Memory CD4 T Cells. J Immunol 2002; 168: 1557-1565.
43. Robinson AT, Miller N, Alexander DR. CD3 antigen-mediated calcium signals and protein kinase C activation are higher in CD45RO+than in CD45RA+human T lymphocyte subsets. Eur J Immunol 1993; 23: 61-68.
44. Gupta M, Satyaraj E, Durdik JM, et al. Differential regulation of T cell activation for primary versus secondary proliferative responses. J Immunol 1997; 158: 4113-4121.
45. Dai Z, Konieczny BT, Lakkis FG. The dual role of IL-2 in the generation and maintenance of CD8+memory T cells. J Immunol 2000; 165: 3031-3036.
46. Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003; 3: 269-279.
47. Goldrath AW, Sivakumar PV, Glaccum M et al. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+T cells. J Exp Med 2002; 195: 1515-1522.
48. Schluns KS, Williams K, Ma A, Zheng XX, Lefrancois L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 2002; 168: 4827-4831.
49. Becker TC, Wherry EJ, Boone D et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 2002; 195: 1541-1548.
50. Kondrack RM, Harbertson J, Tan JT, et al. Interleukin 7 regulates the survival and generation of memory CD4 cells. J Exp Med 2003; 198: 1797-1806.
51. Li J, Huston G, Swain SL. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J Exp Med 2003; 198: 1807-1815.
52. Hancock WW, Wang L, YeQ,et al. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol 2003; 15: 479-486.
53. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998; 338: 1813-1821.
54. Larsen CP, Elwood ET, Alexander DZ et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381: 434-438.
55. Valujskikh A, Pantenburg B, Heeger PS. Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant 2002; 2: 501-509.
56. Williams MA, Onami TM, Adams AB et al. Cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following CD28/CD40 blockade-based regimen. J Immunol 2002; 169: 5387-5391.
57. Welsh RM, Markees TG, Woda BA et al. Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J Virol 2000; 74: 2210-2218.
58. London CA, Lodge MP, Abbas AK. Functional responses and costimulator dependence of memory CD4+T cells. J Immunol 2000; 164: 265-272.
59. Sachs DH, Tolerance. of mice and men. J Clin Invest 2003; 111: 1819-1821.
60. Makhlouf L, Kishimoto K, Smith RN et al. The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade. Diabetes 2002; 51: 3202-3210.
61. Okitsu T, Bartlett ST, Hadley GA, et al. Recurrent autoimmunity accelerates destruction of minor and major histoincompatible islet grafts in nonobese diabetic (NOD) mice.Am J Transplant 2001; 1: 138-145.
62. Cooke A, Phillips JM, Parish NM. Tolerogenic strategies to halt or prevent type 1 diabetes. Nat Immunol 2001; 2: 810-815.
63. Kreuwel HT, Aung S, Silao C, et al. Memory CD8 (+) T cells undergo peripheral tolerance. Immunity 2002; 17: 73-81.
64. Mirshahidi S, Huang CT, Sadegh-Nasseri S. Anergy in peripheral memory CD4 (+) T cells induced by low avidity engagement of T cell receptor. J Exp Med 2001; 194: 719-731.
65. Ahmadzadeh M, Farber DL. Functional plasticity of an antigen-specific memory CD4 T cell population. Proc Natl Acad Sci U S A 2002; 99: 11802-11807.
66. Dai Z, Li Q, Wang Y, et al. CD4+CD25+regulatory T cells suppress allograft rejection mediated by memory CD8+T cells via a CD30-dependent mechanism. J Clin Invest 2004; 113:310-317.
67. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003; 3: 609-620.
68. Yuan X, Salama AD, Dong V et al. The role of the CD134-CD134 ligand costimulatory pathway in alloimmune responses in vivo. J Immunol 2003; 170: 2949-2955.
69. Khayyamian S, Hutloff A, Buchner K et al. ICOS-ligand, expressed on human endothelial cells, costimulates Thl and Th2 cytokine secretion by memory CD4+T cells. Proc Natl Acad Sci U S A 2002; 99: 6198-6203.
70. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345: 248-255.
71. Dedrick RL, Walicke P, Garovoy M. Anti-adhesion antibodies Efal-izumab, a humanized anti-CDl la monoclonal antibody. Trans Immunol 2002; 9: 181-186.
72. Demirci G, Strom TB, Li XC. Islet allograft rejection in nonobese diabetic mice involves the common gamma-chain and CD28/CD 154-dependent and -independent mechanisms.J Immunol 2003;171:3878-3885.