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1.
Induction of suppressive allogeneic regulatory T cells via rabbit antithymocyte polyclonal globulin during homeostatic proliferation in rat kidney transplantation
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Rafael Valdez‐Ortiz Oriol Bestard Inés Llaudó Marcella Franquesa Gema Cerezo Joan Torras Inmaculada Herrero‐Fresneda Ricardo Correa‐Rotter Josep M. Grinyó 《Transplant international》2015,28(1):108-119
Experimental studies have shown that rabbit antithymocyte polyclonal globulin (ATG) can expand human CD4+CD25++Foxp3+ cells (Tregs). We investigated the major biological effects of a self‐manufactured rabbit polyclonal anti‐rat thymoglobulin (rATG) in vitro, as well as its effects on different peripheral T‐cell subsets. Moreover, we evaluated the allogeneic suppressive capacity of rATG‐induced Tregs in an experimental rat renal transplant model. Our results show that rATG has the capacity to induce apoptosis in T lymphocyte lymphocytes as a primary mechanism of T‐cell depletion. Our in vivo studies demonstrated a rapid but transient cellular depletion of the main T cell subsets, directly proportional to the rATG dose used, but not of the effector memory T cells, which required significantly higher rATG doses. After rATG administration, we observed a significant proliferation of Tregs in the peripheral blood of transplanted rats, leading to an increase in the Treg/T effector ratio. Importantly, rATG‐induced Tregs displayed a strong donor‐specific suppressive capacity when assessed in an antigen‐specific allogeneic co‐culture. All of these results were associated with better renal graft function in rats that received rATG. Our study shows that rATG has the biological capacity immunomodulatory to promote a regulatory alloimmune milieu during post‐transplant homeostatic proliferation. 相似文献
2.
Mirko Scarsi Nicola Bossini Fabio Malacarne Francesca Valerio Silvio Sandrini Paolo Airò 《Transplant international》2010,23(8):786-795
To better understand the kinetics of the delayed reconstitution of peripheral CD4+ T‐cells after depletion with a single administration of alemtuzumab (AL) for renal transplantation, we evaluated in these patients the percentage and absolute number of recent thymic emigrants (RTEs) CD4+ T cells, together with naive and memory subsets, defined by the analysis of CD31, CD45RA and CCR7 expression, and compared with patients treated with a nondepleting protocol based on basiliximab, and with healthy controls. In AL‐treated patients, the number of circulating CD4+ T cells was greatly reduced 1 year after the infusion (P < 0.01), but the proportions of central memory, effector memory and terminally differentiated effector memory subsets among CD4+ cells were significantly increased. On the contrary, the proportion and the absolute number of naïve CD4+ T cells, although progressively increasing with time, were severely reduced. In particular, the absolute number of RTEs had only very slight increase with time (P = 0.049) and was dramatically low 1 year after the therapy (P < 0.01 vs. healthy controls; P < 0.05 vs. basiliximab‐treated transplant recipients). These data suggest that a prolonged defective thymic output after AL therapy in renal transplant recipients is one of the main causes of the persistent CD4+ T‐cell lymphopenia observed in these patients. 相似文献
3.
The role of the allograft in the induction of donor-specific T cell hyporesponsiveness 总被引:4,自引:0,他引:4
BACKGROUND: With adequate immunosuppression the majority of renal allografts are accepted, despite the exceptional vigour of the T cell alloimmune response. Previous work from this laboratory has demonstrated that this is accompanied by significant reductions in the precursor frequencies of anti-donor T cells. We have also shown that parenchymal cells are tolerogenic in vitro. We propose that the reduction in T cell frequencies may be due to the interaction between circulating T cells and potentially tolerogenic graft parenchymal cells. Primed/memory T cells (CD45RO+) are the only subset capable of reaching the allograft and therefore we would predict that T cell hyporesponsiveness would develop predominantly in the CD45RO+ subset due to their trafficking properties. METHODS: Frequencies of IL-2 secreting CD45RA+ and CD45RO+ CD4+ T cells in response to donor and third party stimulator cells were estimated in a series of renal transplant recipients, both before and after transplantation. RESULTS: There were highly significant reductions in the frequencies of donor-specific CD4+CD45RO+ T cells, when adjusted to control for the generalised effects of immunosuppression. There were no significant alterations in the frequencies of donor-specific CD4+CD45RA+ T cells. CONCLUSIONS: In renal transplant recipients, donor-specific CD4+ T cell hyporesponsiveness occurs predominantly in CD4+ CD45RO+ T cells which is the subset capable of trafficking through the graft. 相似文献
4.
免疫记忆是机体免疫应答的主要特征之一。目前根据T淋巴细胞表面CD45RA、CD62L及CCR7的表达情况将T细胞划分为初始T细胞(na?ve T cells)、中心记忆T细胞(central memory T cells,TCM)、效应记忆T细胞(effector memory T cells,TEM) 。因TCM和TEM在组织分布及功能上的差异,在抗肿瘤及抗感染免疫中有着重要意义,是近年来研究的热点。 相似文献
5.
6.
Expression of CD39 by Human Peripheral Blood CD4+CD25+ T Cells Denotes a Regulatory Memory Phenotype
K. M. Dwyer D. Hanidziar P. Putheti P. A. Hill S. Pommey J. L. McRae A. Winterhalter G. Doherty S. Deaglio M. Koulmanda W. Gao S. C. Robson T. B. Strom 《American journal of transplantation》2010,10(11):2410-2420
We have shown that CD39 and CD73 are coexpressed on the surface of murine CD4+Foxp3+ regulatory T cells (Treg) and generate extracellular adenosine, contributing to Treg immunosuppressive activity. We now describe that CD39, independently of CD73, is expressed by a subset of blood‐derived human CD4+CD25+CD127lo Treg, defined by robust expression of Foxp3. A further distinct population of CD4+CD39+ T lymphocytes can be identified, which do not express CD25 and FoxP3 and exhibit the memory effector cellular phenotype. Differential expression of CD25 and CD39 on circulating CD4+ T cells distinguishes between Treg and pathogenic cellular populations that secrete proinflammatory cytokines such as IFNγ and IL‐17. These latter cell populations are increased, with a concomitant decrease in the CD4+CD25+CD39+ Tregs, in the peripheral blood of patients with renal allograft rejection. We conclude that the ectonucleotidase CD39 is a useful and dynamic lymphocytes surface marker that can be used to identify different peripheral blood T cell‐populations to allow tracking of these in health and disease, as in renal allograft rejection. 相似文献
7.
Sun L, Yi S, O’Connell PJ. Foxp3 regulates human natural CD4+CD25+ regulatory T‐cell‐mediated suppression of xenogeneic response. Xenotransplantation 2010; 17: 121–130. © 2010 John Wiley & Sons A/S. Abstract: Backgrounds: Cellular rejection of xenografts is predominantly mediated by CD4+ T cells. Foxp3 expressing human naturally occurring CD4+CD25+ regulatory T cells (nTregs) have been shown to suppress pathological and physiological immune responses, including the CD4+ T‐cell‐mediated anti‐pig xenogeneic response in vitro. Although Foxp3 is required for nTreg development and their function, the precise role of Foxp3 in regulating Treg suppressive function in xenoimmune response remains to be identified. Methods: In vitro expanded human nTregs were transfected with fluorescein isothiocyanate ‐conjugated Foxp3 small interfering RNA (siRNA) by Lipofectamine 2000. Transfected nTregs were sorted by fluorescence‐activated cell sorting, and then analyzed for Foxp3 gene and protein expression as well as their phenotypic characteristics. Human CD4+CD25? T cells were stimulated with xenogeneic pig peripheral blood mononuclear cell in the presence or absence of nTregs in a coculture or transwell system for evaluation of nTreg suppressive activity. The production of effector cytokines by xenoreactive CD4+CD25? T cells as well as suppressive cytokine by nTregs in their cocultures was examined by ELISA. Results: The siRNA‐mediated Foxp3 knockdown resulted in impaired nTreg anergic state, downregulated expression of nTreg function associated molecules, and reduced production of suppressive cytokines by nTregs, which together leading to impaired nTreg‐mediated suppression of CD4+CD25? T‐cell proliferation and their effector cytokine production in response to xenogeneic stimulation. Conclusions: This study demonstrates that Foxp3 expression is required for human nTregs to maintain their suppressive function in the xenoimmune response. 相似文献
8.
Presence of Functional Mouse Regulatory CD4+CD25+T Cells in Xenogeneic Neonatal Porcine Thymus-Grafted Athymic Mice 总被引:1,自引:0,他引:1
Z. Sun L. Zhao H. Wang L. Sun H. Yi Y. Zhao 《American journal of transplantation》2006,6(12):2841-2850
Xenotransplantation with porcine thymus is emerging as a possible means to reconstitute host cellular immunity and to induce immune tolerance in rodents and large animals. However, the presence of regulatory T cells (Treg cells) in this model needs to be determined. We herein demonstrated that efficient repopulation of mouse CD4+CD25+Treg cells was achieved in Balb/c nude mice by grafting neonatal porcine thymic tissue (NP THY). Mouse CD4+CD25+T cells expressed normal levels of Foxp3 in NP THY-grafted nude mice. Furthermore, these CD4+CD25+Treg cells showed significant inhibitory effects on the cell proliferation or interleukin-2 products of syngeneic T cells to alloantigens, Con A or a peptide antigen, although the potent immunosuppressive function might be lower than CD4+CD25+Treg cells in Balb/c mice. CD4+CD25+T cells in NP THY-grafted nude mice showed significantly stronger inhibition on the response to donor porcine antigens of CD4+CD25(-)T cells than CD4+CD25+Treg cells in Balb/c mice. Both CD4+CD25+Treg cells in NP THY-grafted nude and Balb/c mice prevented the development of autoimmune disease mediated by syngeneic CD4+CD25(-)T cells in a similar efficient way in the secondary recipients. These findings provide evidence for the potential involvement of CD4+CD25+Treg cells in keeping self-tolerance and transplant tolerance in this xeno-thymus transplantation model. 相似文献
9.
Macedo C Donnenberg A Popescu I Reyes J Abu-Elmagd K Shapiro R Zeevi A Fung JJ Storkus WJ Metes D 《Transplant immunology》2005,14(2):109-116
Immune responses to EBV in immunosuppressed (IS) solid organ transplant (SOTx) recipients have not been well characterized. Here we evaluate the phenotype and function of EBV-specific CD8+ T cells in peripheral blood isolated from "stable" IS SOTx recipients. The EBV-specific CD8+ T cell memory subset distribution in the peripheral blood of patients was examined by flow cytometric analysis using HLA-A2 tetramers incorporating BMLF1 (lytic), and LMP2 and EBNA3A (latent)-derived peptides, in conjunction with mAbs against the CD45RO, CD45RA, and CD62L markers. The ability of CD8+ T cells to produce IFN-gamma in response to the same EBV-derived peptides was measured by ELISPOT assay. Patients and healthy normal donors exhibited similar anti-EBV CD8+ T cell frequencies and specificities against the EBV epitopes evaluated. When compared to healthy normal donors, an overall significant expansion of the CD8+ T cell "effector memory" (CD45RO+/CD62L-) pool, including that of EBV "latent" (LMP2 and EBNA3A)-specific CD8+ T cells was detected in IS SOTx patients. However, the patients' EBV-specific CD8+ T cells showed decreased IFN-gamma production to the EBV-peptide stimulation. These results indicate that the impairment of EBV-specific CD8+ T cell activity is not due to clonal depletion, but is mainly due to impaired functional activation. 相似文献
10.
Stachowski J Barth C Michałkiewicz J Krynicki T Jarmoliński T Runowski D Lewandowska-Stachowiak M Zaniew M Warzywoda A Bortkiewicz E Dobosz M Maciejewski J Baldamus CA 《Pediatric nephrology (Berlin, Germany)》2000,14(8-9):779-785
T cells are involved in the pathogenesis of nephrotic syndrome (NS). The aim of the study was to determine whether the activity
of T-helper-1 (Th1) and T-helper-2 (Th2) cells and the distribution of the lymphocyte subsets, namely CD45RA+CD4+ (”naive”
helper T cells, suppressor-inducer), CD45RA+CD8+ (”naive” suppressor T cells, suppressor-effector), CD45RO+CD4+ (”memory”
helper T cells), are predictive for steroid sensitivity in children with primary NS. These parameters were assessed at the
onset of disease, before initiation of steroid therapy. Two groups of NS children were retrospectively formed according to
steroid sensitivity (SS) or resistance (SR). The activity of Th1 and Th2 cells was defined by the production of interleukin-2
(IL-2), interferon-γ, IL-4, and IL-10 in the supernatants of CD4+ T cell cultures activated with autologous monocytes presenting
tetanus toxoid (TT). Peripheral lymphocyte subsets were determined using double- or triple-color flow cytometry. In SS children
with NS we found a decreased proliferative response of CD4+ T cells to TT stimulation, cytokine synthesis indicating the predominance
of Th2 activity, and an increased percentage of activated suppressor-inducer (CD45RA+ CD4+CD25+, 5.18±0.8, P<0.001) and suppressor-effector (CD45RA+CD8+CD25+, 2.05±0.6, P<0.01) cells, with the concomitant reduction of activated memory cells (CD45RO+CD4+CD25+, 0.2±0.1, P<0.001). In children with SRNS we found an increased proliferative response of CD4+ T cells to TT, a rise in activated memory
(CD45RO+CD4+CD25+, 3.82±0.7, P<0.01) and suppressor-inducer peripheral T cells (CD45RA+ CD4+CD25+, 3.85±0.6, P<0.01), but a low percentage of activated suppressor-effector (CD45RA+CD8+ CD25+, 0.5±0.2, P<0.05) T cells. We conclude that prior to treatment the distribution of lymphocyte subpopulations in peripheral blood together
with Th1 and Th2 cell activity provides a useful tool for evaluating the likelihood of steroid sensitivity in patients with
primary NS.
Received: 3 November 1998 / Revised: 1 September 1999 / Accepted: 8 September 1999 相似文献
11.
N. Gagliani T. Jofra A. Valle A. Stabilini C. Morsiani S. Gregori S. Deng D. M. Rothstein M. Atkinson M. Kamanaka R. A. Flavell M. G. Roncarolo M. Battaglia 《American journal of transplantation》2013,13(8):1963-1975
12.
Oriol Bestard Linda Cassis Josep M. Cruzado Joan Torras Marcella Franquesa Salvador Gil‐Vernet Marc Lucia Josep M Grinyó 《Transplant international》2011,24(5):451-460
The advent of novel immunosuppressive strategies in renal transplantation, with immunomodulatory properties, might facilitate long‐term allograft survival. T‐cell depletion, costimulation‐blockade and mTor inhibition have been shown to favour anti‐donor hyporesponsiveness. Recently, the combination of rATG, belatacept (Bela) and sirolimus (SRL) has been used in kidney transplantation, showing very low incidence of acute rejection and excellent 12‐month graft and patient survival. Herein, we have analysed the 1‐year evolution of memory/effector and regulatory T cells and assessed the donor‐specific T‐cell alloimmune response in a group of these patients and compared with others treated with a calcineurin‐inhibitor(CNI)‐based (rATG/tacrolimus/MMF), and two other Bela‐based regimens (rATG/Bela/MMF and basiliximab/Bela/MMF/steroids). During the first year after transplantation, patients receiving rATG/Bela/SRL had significantly higher percentage of Tregs upon the memory T‐cell compartment and showed a potent anti‐donor suppressive activity. In an in vitro naive and memory/effector T‐cell co‐culture, the combination of costimulation‐blockade and SRL could abrogate both antigen‐specific T‐cell responses as efficiently as using a CNI drug. The combination of T‐cell depletion, costimulation‐blockade and mTor inhibition seems to be able to allow Treg survival and inhibit donor‐specific alloreactive effector immune responses after kidney transplantation in humans. 相似文献
13.
Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients
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M. B. Ezzelarab H. Zhang H. Guo L. Lu A. F. Zahorchak R. W. Wiseman M. A. Nalesnik J. K. Bhama D. K. C. Cooper A. W. Thomson 《American journal of transplantation》2016,16(7):1999-2015
The ability of regulatory T cells (Treg) to prolong allograft survival and promote transplant tolerance in lymphodepleted rodents is well established. Few studies, however, have addressed the therapeutic potential of adoptively transferred, CD4+CD25+CD127?Foxp3+ (Treg) in clinically relevant large animal models. We infused ex vivo–expanded, functionally stable, nonselected Treg (up to a maximum cumulative dose of 1.87 billion cells) into antithymocyte globulin–lymphodepleted, MHC‐mismatched cynomolgus monkey heart graft recipients before homeostatic recovery of effector T cells. The monkeys also received tacrolimus, anti–interleukin‐6 receptor monoclonal antibodies and tapered rapamycin maintenance therapy. Treg administration in single or multiple doses during the early postsurgical period (up to 1 month posttransplantation), when host T cells were profoundly depleted, resulted in inferior graft function compared with controls. This was accompanied by increased incidences of effector memory T cells, enhanced interferon‐γ production by host CD8+ T cells, elevated levels of proinflammatory cytokines, and antidonor alloantibodies. The findings caution against infusion of Treg during the early posttransplantation period after lymphodepletion. Despite marked but transient increases in Treg relative to endogenous effector T cells and use of reputed “Treg‐friendly” agents, the host environment/immune effector mechanisms instigated under these conditions can perturb rather than favor the potential therapeutic efficacy of adoptively transferred Treg. 相似文献
14.
Hélène Longuet Bénédicte Sautenet Philippe Gatault Gilles Thibault Christelle Barbet Jean‐Frédérique Marliere Jean‐Michel Halimi Yvon Lebranchu Christophe Baron Matthias Büchler 《Transplant international》2014,27(3):271-279
To describe long‐term CD4+ T‐cell reconstitution after rabbit antithymocyte globulin (rATG) treatment and identify predictive factors following kidney transplantation. A single‐center retrospective study analyzed lymphocyte subsets in rATG‐treated kidney transplant recipients (1986–2009). 589 patients were analyzed (maximum follow‐up 21 years). A comparator group (n = 298) received an anti‐IL‐2 receptor monoclonal antibody. CD4+ T‐cell lymphopenia (<200/mm3) was present in 48.5%, 9.2%, 6.7%,2.0%, and 0% of patients at one, three, five, 10, and 20 years post‐transplant, respectively. CD4+ T‐cell count increased during the first 10 years but remained below the pretransplant count even after 20 years. At 1, 3, and 6 months post‐transplant, mean CD4+ T‐cell count was significantly lower in patients with CD4+ T‐cell lymphopenia at 12 months versus patients without lymphopenia. On multivariate analyses, significant independent predictors for long‐term impaired CD4 T‐cell reconstitution were recipient age, pretransplant CD4+ T‐cell count, 12‐month CD4+ T‐cell count, and tacrolimus or MMF therapy. Recipient age >40 years was identified as a cutoff point. CD4+ T‐cell reconstitution following rATG treatment remains impaired even after 21 years. Most risk factors for long‐term impaired CD4+ T‐cell reconstitution may be evaluated pretransplant or are modifiable post‐transplant. 相似文献
15.
Volker Daniel Cord Naujokat Mahmoud Sadeghi Rolf Weimer Fabrice Renner Sevgi Yildiz Gerhard Opelz 《Transplant international》2008,21(7):646-660
There is evidence that interferon-gamma (IFN-gamma)-dependent interactions of dendritic cell (DC), T regulatory (Treg), and T suppressor (Ts) subpopulations contribute to allograft acceptance. We measured DC subsets, CD3+CD4+CD25+ (Treg phenotype) and CD3+CD8+CD28(-) (Ts phenotype) peripheral blood lymphocytes (PBL) expressing Foxp3, Th1 or Th2 cytokines, peripheral T- and B-cell counts, and plasma cytokines in 33 kidney transplant recipients with a serum creatinine of < or =1.8 mg/dl and 32 recipients with a serum creatinine of > or =2.0 mg/dl more than 100 days post-transplant. Cell subsets were measured in whole blood using four-color flow cytometry. Patients with increased creatinine had less frequently detectable CD3+CD4+CD25+IFN-gamma+ PBL than patients with good graft function (P = 0.017). In patients with good graft function, CD3+CD4+CD25+IFN-gamma+ PBL were associated with high Foxp3+, IL-2+, IL-12+, IL-4+, and IL-10+ CD3+CD4+CD25+ T PBL (P < 0.001), low CD3+CD8+CD28(-)Foxp3+ (P = 0.002), CD3+CD4+DR+ (P = 0.002), CD3+CD8+DR+ T (P = 0.005) and CD19+ B PBL (P = 0.005), and low lineage(-)HLA-DR+CD11c+CD123(-) DC1 (P = 0.006). Patients with impaired graft function did not show these associations. Additional flow cytometric analysis confirmed strong co-expression of IFN-gamma and Foxp3 by CD4+CD25+ PBL particularly in patients with good graft function. Our data support an immunoregulatory role of CD3+CD4+CD25+Foxp3+IFN-gamma+ cells in a subgroup of transplant recipients with good graft acceptance. 相似文献
16.
K. L. Hippen S. C. Merkel D. K. Schirm C. Nelson N. C. Tennis J. L. Riley C. H. June J. S. Miller J. E. Wagner B. R. Blazar 《American journal of transplantation》2011,11(6):1148-1157
Adoptive transfer of thymus‐derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft‐versus‐host disease (GVHD). TGFß induces Foxp3 expression and suppressive function in stimulated murine CD4+25‐ T cells, and these induced Treg (iTregs), like nTreg, suppress auto‐ and allo‐reactivity in vivo. However, while TGFß induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGFß‐dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25–45RA+) T cells. Rapa/TGFß iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL‐2, IFNγ or IL‐17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGFß induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ~240 × 109 (range ~70–560 × 109) iTregs from CD4+25‐ T cells in ≤2 weeks of culture. Most importantly, Rapa/TGFß iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases. 相似文献
17.
A. M. Woltman S. W. van der Kooij J. W. de Fijter C. van Kooten 《American journal of transplantation》2006,6(11):2580-2591
Dendritic cells (DCs) play a crucial role in the induction of antigen-specific immunity and tolerance. Considering in vivo application of DCs prior to human organ transplantation, a protocol to develop tolerogenic DCs that not only induce unresponsiveness in naive (CD45RA+) T cells, but also in alloreactive memory (CD45RO+) T cells is required. The present study shows that dexamethasone (Dex) alters the differentiation of human monocyte-derived DCs. DexDCs cocultured with allogeneic CD4+ T cells induced low proliferating and low IFNgamma producing T cells. This is caused by lack of both costimulation via CD28 and hampered production of a soluble factor, as well as additional active suppression via B7-H1 and IL-10. T cells primed by DexDCs demonstrated hyporesponsiveness upon restimulation with mature DCs seemingly via the induction of anergy, since these cells showed no enhanced apoptosis and only a limited suppressive capacity. Interestingly, not only cocultures of allogeneic CD45RA+, but also of CD45RO+ T cells with DexDCs rendered T-cell populations hyporesponsive to restimulation with mature DCs. The finding that also alloreactive memory T cells can be regulated supports the rationale of cell-based therapies to obtain allograft-specific tolerance in transplant recipients. 相似文献
18.
BackgroundCorneal transplantations (CTXs) are a vision-saving procedure. Routinely, while CTXs' survival rates remain high, the risk of graft failure increases significantly for repeated CTXs. The reason is an alloimmunization following previous CTXs and development of memory T (Tm) and B (Bm) cells.MethodsWe characterized populations of cells present in explanted human corneas from patients receiving the first CTX and marked as a primary CTX (PCTX) or the second or more CTXs and marked as a repeated CTX (RCTX). Cells extracted from resected corneas and from peripheral blood mononuclear cells (PBMCs) were analyzed by the flow cytometry method using multiple surface and intracellular markers.ResultsOverall, the number of cells was similar in PCTX and RCTX patients. Extracted infiltrates from PCTXs and RCTXs contained similar numbers of T cell subsets, namely CD4+, CD8+, CD4+ Tm, CD8+ Tm, CD4+Foxp3+ T regulatory (Tregs), CD8+ Treg cells, while very few B cells (all p = NS). However, when compared to peripheral blood, PCTX and RCTX corneas contained significantly higher percentages of effector memory CD4+ and CD8+ T cells (both p < 0,05). In comparison to PCTX, RCTX group had the highest levels of Foxp3 in T CD4+ Tregs (p = 0,04) but decreased percentage of Helios-positive CD4+ Tregs.ConclusionPCTXs and especially RCTXs are rejected mainly by local T cells. The accumulation of effector CD4+ and CD8+ T cells, as well as CD4+ and CD8+ Tm cells is associated with the final rejection. Furthermore, local CD4+ and CD8+ Tregs expressing Foxp3 and Helios are probably insufficient to impose the acceptance of CTX. 相似文献
19.
Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney–Bone Marrow Transplantation to Induce Transplantation Tolerance
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T. M. Savage T. Morokata A. Obradovic S. A. LoCascio B. Shonts J. Zuber S. P. Lau R. Shah H. Morris V. Steshenko E. Zorn F. I. Preffer S. Olek D. M. Dombkowski L. A. Turka R. Colvin R. Winchester T. Kawai M. Sykes 《American journal of transplantation》2017,17(8):2020-2032
We examined tolerance mechanisms in patients receiving HLA‐mismatched combined kidney–bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high‐throughput sequencing of T cell receptor‐β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non‐Tregs revealed marked early enrichment of Tregs (CD3+CD4+CD25highCD127lowFoxp3+) in blood that resulted from peripheral proliferation (Ki67+), possibly new thymic emigration (CD31+), and, in one tolerant subject, conversion from non‐Tregs. Among recovering conventional T cells, central memory CD4+ and CD8+ cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor‐reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia‐driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells. 相似文献
20.
Stauch D Yahyazadeh A Bova R Melloh GC Füldner A Baron U Olek S G?ldner K Weiss S Pratschke J Kotsch K 《Transplant international》2012,25(3):302-313
T‐cell‐depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting. Besides prevention of alloreactivity, treatment with rabbit antithymocyte globulin (rATG) has been related to the induction of immunoregulatory T cells (Treg) in vitro and in vivo. To investigate Treg induced by rATG, we prospectively studied the effect of rATG induction therapy in liver‐transplanted recipients in vivo (n = 28). Treg induction was further evaluated by means of Treg‐specific demethylation region (TSDR) analysis within the FOXP3 locus. Whereas no induction of CD4+ CD25highCD127? Treg could be observed by phenotypic analysis, we could demonstrate an induction of TSDR+ T cells within CD4+ T cells exclusively for rATG‐treated patients in the long‐term (day 540) compared with controls (P = NS). Moreover, although in vitro experiments confirm that rATG primarily led to a conversion of CD4+ CD25? into CD4+ CD25+ T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern. Consequently, the generation of Treg after rATG co‐incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined. 相似文献