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Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery 总被引:11,自引:0,他引:11
BACKGROUND: Rapamycin (Rapa) is an immunosuppressant that is used in patients and animal models to control allograft rejection. Its mechanisms of action are not fully understood. In this article, the authors have investigated the effects of therapeutic doses of Rapa on both thymic and peripheral T-cell populations in the adult rat. METHODS: The therapeutic dosage of Rapa was optimized using cardiac transplantation between LEW and DA rats. Thymic morphology was assessed by hematoxylin-eosin staining. Flow cytometric analysis was performed to analyze T-cell phenotype and apoptosis. T-cell receptor (TCR)-mediated T-cell responsiveness was evaluated by 3[H]-thymidine deoxyribose incorporation. RESULTS: Rapa induced atrophy in the thymus but not in peripheral lymphoid organs. Moreover, fibrosis occurred in thymus that was long-lasting after Rapa withdrawal. In animals treated with Rapa, there was a significant reduction in CD4+CD8+ thymocytes caused by accelerated apoptosis, whereas CD4-CD8-, CD4+CD8-, and CD8+CD4- populations remained unaffected. In contrast, the cellularity of the periphery lymphoid organs was not altered. Within the CD4+ thymocyte population, CD4+CD25+ thymocytes were resistant to Rapa-accelerated apoptosis, and in the periphery, the ratio of CD4+CD25+ to CD4+CD25- T cells was increased. Notably, the peripheral CD4+CD25+ T cells were hyporesponsive to TCR-mediated activation. CONCLUSIONS: The resistance of the peripheral CD4+CD25+ T cells to Rapa treatment might contribute to its immunosuppressive action. The long-term effects of Rapa on thymus atrophy and thymocyte development requires consideration with respect to its clinical application. 相似文献
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Yuling H Ruijing X Xiang J Yanping J Lang C Li L Dingping Y Xinti T Jingyi L Zhiqing T Yongyi B Bing X Xinxing W Youxin J Fox DA Lundy SK Guohua D Jinquan T 《Journal of the American Society of Nephrology : JASN》2008,19(11):2130-2139
The source of IgA and the mechanism for deposition of IgA in the mesangium remain unknown for primary IgA nephropathy. Because CD19(+)CD5(+) B cells are important producers of IgA and contribute to several autoimmune diseases, they may play an important role in IgA nephropathy. In this study, flow cytometry, quantitative PCR, and confocal microscopy were used to assess the frequency, distribution, Ig production, CD phenotypes, cytokine production, and sensitivity to apoptosis of CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney biopsies of 36 patients with primary IgA nephropathy. All patients with IgA nephropathy were significantly more likely to have CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney biopsies than were five control subjects and 10 patients with active systemic lupus erythematosus. The 33 patients who had IgA nephropathy and responded to treatment demonstrated a significant decrease in CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney (all P < 0.01). In the three patients who had IgA nephropathy and did not respond to treatment, the frequency of CD19(+)CD5(+) B cells did not change. CD19(+)CD5(+) B cells isolated from patients with untreated IgA nephropathy expressed higher levels of IgA, produced more IFN-gamma, and were more resistant to CD95L-induced apoptosis than cells isolated from control subjects and patients with lupus; these properties reversed with effective treatment of IgA nephropathy. In conclusion, these results strongly suggest that CD19(+)CD5(+) B cells play a prominent role in the pathogenesis of primary IgA nephropathy. 相似文献
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BACKGROUND: Injection of neonatal BALB/c mice with semi-allogeneic splenocytes leads to antigen-specific tolerance lasting into adulthood. Tolerant mice accept A/J skin grafts and fail to generate CD8 cytotoxic T lymphocyte (CTL) activity against A/J targets. Anergic CD8 T cells are present in tolerant mice, and CD4 regulatory cells function to maintain CD8 cell anergy. METHODS: Neonatal BALB/c mice were injected with 108 live CAF, splenocytes, and mice were deemed tolerant by accepting A/J grafts over 40 days. CD8 cell proliferation was measured by in vitro incorporation of bromodeoxyuridine coupled with fluorescence-activated cell sorter analysis. Alloantigen-specific cytotoxicity was tested using 51Cr release assays of A/J or third-party targets. RESULTS: We demonstrate that A/J-specific anergic CD8 cells are present in neonatal primed mice that develop tolerance but not in neonatal primed mice that reject A/J skin grafts. Anergic CD8 cells show decreased proliferation and no CTL activity against A/J targets. Addition of interleukin-2 (IL-2) to unfractionated cultures fails to restore CTL activity against A/J targets. However, addition of IL-2 to CD4-depleted cultures restores A/J-specific CD8 CTL activity. Removal of CD4+/CD25+ cells, but not CD4+/CD25- cells, also restores CD8 CTL activity against A/J in the presence, but not the absence, of IL-2. Moreover, when added back into cultures, purified CD4+/CD25+ cells from tolerant mice inhibit the generation of CD8 CTL against A/J targets. CONCLUSION: These data indicate that CD8 anergy is associated with the state of tolerance, and that CD4+CD25+ cells from tolerant mice function to maintain A/J-specific CD8 cell anergy in vitro. 相似文献
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目的探讨CD3、CD57、CD20细胞在原发性肝细胞癌(HCC)、癌旁、肝硬化及正常肝组织中的数量及意义.方法HCC 60例,单纯性肝硬化62例,正常肝组织23例,以免疫组化SP法进行CD3、CD57、CD20染色,对阳性细胞数进行定量分析并与临床资料进行相关探讨.结果(1)各组CD3+细胞平均数从高到低为癌旁组织、癌组织、肝硬化组织、正常肝组织(P<0.05);各组CD57+细胞平均数从高到低为癌组织、癌旁组织、正常肝组织、肝硬化组织(P <0.05);各组CD20+细胞平均数从高到低为癌组织、癌旁组织、肝硬化组织、正常肝组织(P <0.01).(2)HCC中CD3+细胞、CD57+细胞、CD20+细胞与组织学分级均无明显关系.(3)HCC中CD57+细胞和CD20+细胞随着临床分期的发展有下降的趋势(P <0.05);HCC中CD3+细胞平均数与临床TNM分期无关.(4)HCC中15月内有转移组的CD57+、CD3+细胞数均少于无转移组(P<0.01).HCC患者15月内有无转移与HCC和癌旁组织中的B细胞分布均无关.结论临床上,随着HCC患者的病情恶化,CD3+、CD57+、CD20+细胞逐渐减少.CD3+、CD57+、CD20+细胞可成为反映机体抗肿瘤特异性细胞免疫状态和生物学行为及判断患者预后的重要指标. 相似文献
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目的:探讨血清微环境对小鼠T细胞衰老的调节作用。方法:分别取年老(12~14月龄)及年轻(1.5~2月龄)小鼠各10只,提取其脾脏淋巴细胞及血清,实验分4组。组I为年老鼠T淋巴细胞+10%年轻鼠血清;组II为年老鼠T淋巴细胞+10%年老鼠血清;组III为年轻鼠T淋巴细胞+10%年轻鼠血清;组IV为年轻鼠T淋巴细胞+10%年老鼠血清。培养48h后,经流式细胞术研究CD8+CD28+共表达率差异。结果:组I和组II T细胞表面的CD8+CD28+共表达率分别是(10.84±0.6841)%和(3.18±0.1789)%,组III和组IV T细胞表面的CD8+CD28+共表达分别是(12.5±0.9445)%和(8.36±0.2074)%。各组间对比有统计学差异(P〈0.05)结论:血清微环境具有调节小鼠T细胞衰老的作用,年轻鼠血清能使年老鼠的T细胞表面的CD8+CD28+共表达率提高,年老鼠的血清能使年轻鼠的T细胞表面的CD8+CD28+共表达率降低。 相似文献
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Oluwole SF Oluwole OO DePaz HA Adeyeri AO Witkowski P Hardy MA 《Transplant immunology》2003,11(3-4):287-293
The Holy Grail of clinical organ transplantation is the safe induction of allograft tolerance. Transplant tolerance has been successfully induced in animal models. Since T cells play a pivotal role in graft rejection, modulating T cell function has been the primary focus of studies aimed at inducing transplant tolerance. Rodent models of transplant tolerance induction include central deletion and peripheral mechanisms involving activation-induced cell death (AICD), anergy, immune deviation, and production of regulatory T cells. These mechanisms are not mutually exclusive. Although clonal deletion and anergy limit self-reactive T cells in the thymus, these mechanisms alone are not sufficient for controlling self-reactive T cells in the periphery. There is now evidence that the adult animal harbors two functionally distinct populations of CD4(+) T cells; one mediates autoimmune disease and the other dominantly inhibits it. The latter cells express CD4, CD25 and CTLA-4. These thymus-derived T cells have recently been shown to mediate the induction and maintenance of transplant tolerance. These CD4(+)CD25(+) T cells are similar in origin, phenotype, and function to those that maintain natural self-tolerance and T cell homeostasis in the periphery. Against this background, is it possible that alloantigen specific regulatory T cells might be generated and expanded ex vivo before organ transplantation and then infused to induce long-term tolerance, perhaps without the need for chronic immunosuppression? 相似文献
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Zegleń S Łaszewska A Wojarski J Woźniak-Grygiel E Zakliczyński M Ochman M Wilczek P Karolak W Nożyński J Zembala M 《Transplantation proceedings》2011,43(8):3055-3057
Introduction
The aim of this study was to assess peripheral blood lymphocyte subtypes (CD3+, CD19+, CD16+CD56+, CD4+, CD8+, and CD3+HLA-DR+) obtained from thoracic organ recipients at various periods after transplantation.Material and Methods
Seventeen patients after lung transplantation (LT) and 5 patients after heart transplantation (HT) included 13 males (76.5%) and 4 females (23.5%) of overall mean age at the time of transplantation of 46.7 ± 11.55 years and mean body mass index of 21.1 ± 4. Lymphocyte phenotypes were estimated using Simultest IMK Plus.Results
A significant decrease in lymphocytes of the majority of subtypes was observed at 1 year posttransplantation compared with normal ranges: CD19+ B lymphocytes in 56% of patients, CD8+ T cells among 48% and CD16+CD56+ natural killer elements, 56%. In contrast, there were increased numbers of activated lymphocytes (CD3+HLA-DR+). Beyond the 1-year observation, we observed a trend to normalize parameters among the majority of subjects.Conclusion
A clear tendency to a decrease number of peripheral blood lymphocytes of various subtypes was observed among thoracic organ recipients in the first year posttransplantation with the exception of activated HLA-DR+ cells. After the first year, there was slow restoration of lymphocytes. 相似文献13.
C. Scottà J. Canavan F. C. Edozie H. Fazekasova G. M. Lord S. John L. D. Barber M. P. Hernandez‐Fuentes G. Lombardi 《American journal of transplantation》2011,11(8):1734-1742
Successful expansion of functional CD4+CD25+ regulatory T cells (Treg) ex vivo under good manufacturing practice conditions has made Treg‐cell therapy in clinical transplant tolerance induction a feasible possibility. In animals, Treg cells home to both transplanted tissues and local lymph nodes and are optimally suppressive if active at both sites. Therefore, they have the opportunity to suppress both naïve and memory CD4+CD25? T cells (Tresp). Clinical transplantation commonly involves depleting therapy at induction (e.g. anti‐CD25), which favors homeostatic expansion of memory T cells. Animal models suggest that Treg cells are less suppressive on memory, compared with naïve Tresp that mediate allograft rejection. As a result, in the context of human Treg‐cell therapy, it is important to define the effectiveness of Treg cells in regulating naïve and memory Tresp. Therefore, we compared suppression of peripheral blood naïve and memory Tresp by fresh and ex vivo expanded Treg cells using proliferation, cytokine production and activation marker expression (CD154) as readouts. With all readouts, naïve human Tresp were more suppressible by approximately 30% than their memory counterparts. This suggests that Treg cells may be more efficacious if administered before or at the time of transplantation and that depleting therapy should be avoided in clinical trials of Treg cells. 相似文献
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Kamil Torres Anna Torres Andrzej Chrościcki Ryszard Maciejewski Sebastian Radej Jacek Roliński Łukasz Pietrzyk Grzegorz Wallner 《Surgical endoscopy》2013,27(3):872-879
Background
Obesity has become a global epidemic and a leading metabolic disease in the world. Laparoscopic surgeries may influence the function of the immunologic system. The percentages of CD4+ and CD8+ T lymphocyte cells have been described as prognostic factors for patients undergoing abdominal surgeries. This study aimed to evaluate the changes in CD4+ and CD8+ T lymphocyte cells, the ratio of CD4+ to CD8+ cells, and the ZAP-70 kinase expression on T CD3+ and B CD19+ cells in obese and normal-weight individuals undergoing laparoscopic cholecystectomy (LC).Methods
The study group consisted of 46 asymptomatic patients with gallstones shown by ultrasound examination but without signs of any gallbladder complications. The patients underwent planned LC. Blood samples were obtained at three times, and the percentages of studied cells were measured by flow cytometry. Patients were enrolled to two groups: N group (body mass index [BMI], ≤25 kg/m2) and O group (BMI, ≥30 kg/m2). For statistical analysis, the Mann–Whitney U test and the Wilcoxon matched-pairs signed-ranks test were used. All p values lower than 0.05 were considered significant.Results
The percentage of CD4+ T cells did not differ between the N and O groups before or after the surgery. Only in the N group did the percentage of CD4+ lymphocytes increase from 0 to 48 h. A higher percentage of CD8+ lymphocytes was observed in the O group postoperatively than in the N group. Differences of ZAP-70 kinase expression in the O group were observed at 24 and 48 h of the study. Decreased expression of ZAP-70 kinase was shown in the N group at both 0–24 and 24–48 h. In the O group, this tendency was noted at 24–48 h.Conclusions
Immunologic activation after LC was confirmed in both weight groups. However, higher modulation, more typical for open surgeries, was observed in the obese group. 相似文献15.
Colovai AI Liu Z Ciubotariu R Lederman S Cortesini R Suciu-Foca N 《Transplantation》2000,69(7):1304-1310
BACKGROUND: The underlying mechanism of immune suppression mediated by regulatory T cells is not completely understood. In previous studies we have shown that antigen-specific human T suppressor cells (Ts) can be generated in vitro by multiple rounds of stimulation with allogeneic, xenogeneic, or antigen-pulsed autologous antigen-presenting cells (APC). Human Ts express the CD8+CD28- phenotype and require specific recognition of MHC class I/peptide complexes on the surface of APC to block proliferation of T helper cells (Th). The aim of the present study was to explore the activation requirements of Ts as well as the nature of Th unresponsiveness to xenogeneic (swine) antigens induced by Ts. METHODS AND RESULTS: We investigated whether specific antigenic stimulation of Ts is required for their ability to inhibit early activation of xenoreactive Th (up-regulation of CD40 ligand). Flow cytometry studies indicated that Ts function required specific recognition of MHC class I on the surface of the stimulating APC. However, neither proliferation nor protein synthesis was required for the ability of Ts to inhibit Th. Ts drastically reduced the capacity of xenoreactive Th cells to produce interleukin (IL)-2 in response to the specific APC, without affecting their surface expression of IL-2 receptor. The suppressor effect that Ts exerted on Th proliferation could not be circumvented by CD40 ligation on the surface of the APC but could be reversed by the addition of exogenous IL-2. CONCLUSION: These data indicate that Ts induce anergy of xenoreactive human Th cells upon specific recognition of MHC class I antigens. Hence, Ts may prevent the activation of T cell-mediated immune responses against xenogeneic transplants. 相似文献
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BACKGROUND: The thymus is a major organ that generates "natural" CD4+CD25+ T regulatory cells (Tregs). However, the detailed pathway(s) by which Tregs are developed remain a mystery. CD28-/- mice have profound decrease in Tregs, but the underlying molecular events remain largely undefined. METHODS: CD4+CD25+ thymocytes from wildtype and CD28-/- mice were cultured with T-cell receptor (TCR) and transforming growth factor (TGF)-beta stimulation to generate CD25+ Tregs and their phenotype and function were studied in vitro and in vivo. RESULTS: TGF-beta induced Foxp3 expression in thymic CD4+CD25+ cells and converted them to CD25+ Tregs. The converted Tregs expressed high levels of CD25, whereas the non-suppressive CD4+ T cells from the control cultures expressed CD25(low). CD28-/- thymic CD4+CD25+ cells showed transit lower levels of Foxp3 upon TCR and TGF-beta stimulation early in culture, but the defect in Foxp3 expression was restored to normal levels after 60-72 hr. Consequently, TGF-beta converted CD28-/- CD25+ cells to CD25+ Tregs that were indistinguishable from those of the wildtype mice. However, the total number of TGF-beta converted CD28-/- Tregs was significantly lower than that of wildtype mice. In vivo, TGF-beta converted CD28-/- CD25+ Tregs were less viable than those from the wildtype mice. Importantly, TGF-beta induced alloantigen specific CD4+CD25+ Tregs from thymic CD25-SP cells which also required CD28 to maintain their survival. CONCLUSIONS: TGF-beta and TCR co-stimulation converts thymic CD4+CD25+ T cells into CD4+CD25+ Tregs by inducing Foxp3, and the contribution of CD28 stimulation to this process is mainly through maintaining survival of the induced Tregs. 相似文献
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目的 观察体外分离的CD4+CD25+调节性T细胞对同种胰岛移植免疫耐受的影响.方法 免疫磁珠法分离CD4+CD25+调节性T细胞,体外试验观察其对CD4+CD25-T细胞增殖的影响.将数量达1×106的CD4+CD25+调节性T细胞回输胰岛移植受体,对比其对移植物存活的影响.结果 分离的CD4+CD25+调节性T细胞体外试验可明显抑制CD4+CD25-T细胞的增殖.单纯胰岛移植组移植物物存活期为(5.57±0.79)d,回输受体CD4+CD25+调节性T细胞数量1×106、2×106时,胰岛移植物存活时间分别为(15.29±2.29)d和(25.43±2.30)d(P《0.01).CD4+CD25+调节性T细胞回输胰岛移植受体可显著延长移植物存活期,诱导免疫耐受的作用为剂量依赖性.结论 CD+CD25+调节性T细胞体外、体内试验可抑制效应性T细胞功能,诱导胰岛移植免疫耐受. 相似文献
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Eliana Mari?o Jeanette Villanueva Stacey Walters David Liuwantara Fabienne Mackay Shane T. Grey 《Diabetes》2009,58(7):1568-1577