共查询到20条相似文献,搜索用时 15 毫秒
1.
Interferon Gamma and Contact‐dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell–Mediated Antibody‐dependent Chronic Rejection 下载免费PDF全文
C. M. Lin R. J. Plenter M. Coulombe R. G. Gill 《American journal of transplantation》2016,16(11):3121-3130
Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor‐specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody‐mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN‐γ) versus the contact‐dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune‐deficient C57BL/6 rag?/?γc?/? recipients, who also received monoclonal anti–major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild‐type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN‐γ–deficient NK cells or host IFN‐γ neutralization led to amelioration of these lesions. Use of either perforin‐deficient NK cells or CD95 (Fas)–deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell–derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN‐γ production and contact‐dependent cytotoxic activity are rate‐limiting effector pathways that contribute to this form of antibody‐induced chronic allograft vasculopathy. 相似文献
2.
G. H. Tse C. J. C. Johnston D. Kluth M. Gray D. Gray J. Hughes L. P. Marson 《American journal of transplantation》2015,15(12):3067-3080
3.
K. Yamaura O. Boenisch T. Watanabe T. Ueno V. Vanguri J. Yang K. Tanaka I. Guleria J. Borst Y. Zhai J. W. Kupiec‐Weglinski N. Najafian 《American journal of transplantation》2010,10(5):1210-1220
CD8+ memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T‐cell costimulatory pathway in alloreactive CD8+/CD4+ T‐cell activation. CD27‐deficient (CD27?/?) and wild‐type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4+ or CD8+ T cells, suggesting that CD27 is not essential during primary T‐cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27?/? or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor‐type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40‐ but not day 10‐sensitized CD27?/? recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8+ T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27?/? recipients of class I‐ but not class II‐mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8+ memory T cells in acute and chronic allograft rejection. 相似文献
4.
CD4 T Cells but Not Th17 Cells Are Required for Mouse Lung Transplant Obliterative Bronchiolitis 下载免费PDF全文
H. Suzuki S. R. Wagner C. Zhang O. W. Cummings L. Fan M. H. Kaplan D. S. Wilkes R. A. Shilling 《American journal of transplantation》2015,15(7):1793-1804
Lung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL‐17. We have used this orthotopic mouse model to investigate the source of IL‐17A and the requirement for T cells producing IL‐17A. The major sources of IL‐17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL‐17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3‐deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL‐17A+ cells was not decreased in mice with STAT3‐deficient T cells due mainly to the presence of IL‐17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL‐17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other. 相似文献
5.
G. Schiechl S. M. Brunner R. Kesselring M. Martin P. Ruemmele M. Mack S. W. Hirt H. J. Schlitt E. K. Geissler S. Fichtner‐Feigl 《American journal of transplantation》2013,13(5):1168-1180
The innate receptor “triggering‐receptor‐expressed‐on‐myeloid‐cells‐1” (TREM‐1) enhances downstream signaling of “pattern recognition receptor” (PRR) molecules implicated in inflammatory responses. However the mechanistic role of TREM‐1 in chronic heart rejection has yet to be elucidated. We examined the effect of TREM‐1+ antigen‐presenting cells (APC) on alloreactive CD4+ lymphocytes. Bm12 donor hearts were transplanted into wild‐type MHC‐class‐II‐mismatched C57BL/6J recipient mice. Progressive allograft rejection of bm12‐donor hearts with decreased organ function, severe vasculopathy and allograft fibrosis was evident within 4 weeks. TREM‐1+CD11b+MHC‐II+F4/80+CCR2+ APC and IFNγ‐producing CD4+ cells were detected during chronic rejection. Peptide inhibition of TREM‐1 attenuated graft vasculopathy, reduced graft‐infiltrating leukocytes and prolonged allograft survival, while being accompanied by sustained low levels of CD4+ and CD8+ cell infiltration. Remarkably, temporary inhibition of TREM‐1 during early immune activation was sufficient for long‐term allograft survival. Mechanistically, TREM‐1 inhibition leads to reduced differentiation and proliferation of IFNγ‐producing Th1 cells. In conclusion, TREM‐1 influences chronic heart rejection by regulating the infiltration and differentiation of CD4+ lymphocytes. 相似文献
6.
Rapamycin Interferes With Postdepletion Regulatory T Cell Homeostasis and Enhances DSA Formation Corrected by CTLA4‐Ig 下载免费PDF全文
B. Oh J. Yoon A. Farris III A. Kirk S. Knechtle J. Kwun 《American journal of transplantation》2016,16(9):2612-2623
Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor‐specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4+CD25+FoxP3+ T reg cell numbers during treatment. On the contrary, ICOS+PD‐1+CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4‐Ig supplementation in conjunction with rapamycin corrected rapamycin‐induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4‐Ig. 相似文献
7.
IL‐17 Deficiency Attenuates Allograft Injury and Prolongs Survival in a Murine Model of Fully MHC‐Mismatched Renal Allograft Transplantation 下载免费PDF全文
T. Kwan S. J. Chadban J. Ma S. Bao S. I. Alexander H. Wu 《American journal of transplantation》2015,15(6):1555-1567
8.
Suheyla Hasgur Ran Fan Daniel B. Zwick Robert L. Fairchild Anna Valujskikh 《American journal of transplantation》2020,20(10):2740-2754
Understanding the mechanisms of T cell homeostatic expansion is crucial for clinical applications of lymphoablative therapies. We previously established that T cell recovery in mouse heart allograft recipients treated with anti‐thymocyte globulin (mATG) critically depends on B cells and is mediated by B cell–derived soluble factors. B cell production of interleukin (IL)‐1β and IL‐6 is markedly upregulated after heart allotransplantation and lymphoablation. Neutralizing IL‐1β or IL‐6 with mAb or the use of recipients lacking mature IL‐1β, IL‐6, IL‐1R, MyD88, or IL‐6R impair CD4+ and CD8+ T cell recovery and significantly enhance the graft‐prolonging efficacy of lymphoablation. Adoptive co‐transfer experiments demonstrate a direct effect of IL‐6 but not IL‐1β on T lymphocytes. Furthermore, B cells incapable of IL‐1β or IL‐6 production have diminished capacity to mediate T cell reconstitution and initiate heart allograft rejection upon adoptive transfer into mATG treated B cell deficient recipients. These findings reveal the essential role of B cell–derived IL‐1β and IL‐6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation. 相似文献
9.
Anti‐huCD20 Antibody Therapy for Antibody‐Mediated Rejection of Renal Allografts in a Mouse Model 下载免费PDF全文
V. Gorbacheva N. Kohei H. Tsuda T. Tanaka N. Dvorina N. Nonomura S. Takahara A. Valujskikh W. M. Baldwin III R. L. Fairchild 《American journal of transplantation》2015,15(5):1192-1204
10.
Jose Marino Bruno Gonzalez‐Nolasco Xianding Wang William Orent Gilles Benichou 《American journal of transplantation》2020,20(9):2551-2558
Alloreactive memory T cells play a key role in transplantation by accelerating allograft rejection and preventing tolerance induction. Some studies using µMT mice, which are constitutionally devoid of B cells, showed that B cells were required for the generation of memory T cells after allotransplantation. However, whether B cell depletion in normal adult mice has the same effect on memory responses by CD4+ and CD8+ T cells activated after transplantation has not been thoroughly investigated. In this study, we tested the effect of anti‐CD20 antibody‐mediated B cell depletion on CD4+ and CD8+ memory T cell alloresponses after skin transplantation in wild‐type mice. We found that B cell depletion prevented the development of memory alloresponses by CD4+ T cells but enhanced that of CD8+ memory T cells. Next, we tested the influence of B cell depletion on hematopoietic chimerism. In OT‐II CD4+ anti‐OVA TCR transgenic mice sensitized to ovalbumin antigen, B cell depletion also impaired allospecific memory T cell responses and thereby enhanced donor hematopoietic chimerism and T cell deletion after bone marrow transplantation. This study underscores the complexity of the relationships between B and T cells in the generation and reactivation of different memory T cell subsets after transplantation. 相似文献
11.
Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model 下载免费PDF全文
Yue Zhao Song Chen Peixiang Lan Chenglin Wu Yaling Dou Xiang Xiao Zhiqiang Zhang Laurie Minze Xiaoshun He Wenhao Chen Xian C. Li 《American journal of transplantation》2018,18(3):604-616
Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor–associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage‐specific deletion of TRAF6 (LysMCreTraf6 fl/fl) or mTOR (LysMCreMtorfl/fl) did not affect acute allograft rejection. However, treatment of LysMCreMtorfl/fl recipients with CTLA4‐Ig induced long‐term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysMCreTraf6 fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4‐Ig–treated LysMCreTraf6 fl/fl mice was similar to that of CTLA4‐Ig–treated wild‐type B6 recipients. Mechanistically, we found that the graft‐infiltrating macrophages in LysMCreMtorfl/fl recipients expressed high levels of PD‐L1, and that PD‐L1 blockade readily induced rejection of otherwise survival grafts in the LysMCreMtorfl/fl recipients. Our findings demonstrate that targeting mTOR‐dependent M2 cells is critical for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD‐1/PD‐L1 coinhibitory pathway. 相似文献
12.
Allergic diseases rob corneal allografts of immune privilege and increase immune rejection. Corneal allograft rejection in BALB/c allergic hosts was analyzed using a short ragweed (SWR) pollen model of allergic conjunctivitis. Allergic conjunctivitis did not induce exaggerated T‐cell responses to donor C57BL/6 (B6) alloantigens or stimulate cytotoxic T lymphocyte (CTL) responses. Allergic conjunctivitis did affect T regulatory cells (Tregs) that support graft survival. Exogenous IL‐4, but not IL‐5 or IL‐13, prevented Treg suppression of CD4+ effector T cells isolated from naïve mice. However, mice with allergic conjunctivitis developed Tregs that suppressed CD4+ effector T‐cell proliferation. In addition, IL‐4 did not inhibit Treg suppression of IL‐4Rα?/? CD4+ T‐cell responses, suggesting that IL‐4 rendered effector T cells resistant to Tregs. SRW‐sensitized IL‐4Rα?/? mice displayed the same 50% graft survival as nonallergic WT mice, that was significantly less than the 100% rejection that occurred in allergic WT hosts, supporting the role of IL‐4 in the abrogation of immune privilege. Moreover, exacerbation of corneal allograft rejection in allergic mice was reversed by administering anti‐IL‐4 antibody. Thus, allergy‐induced exacerbation of corneal graft rejection is due to the production of IL‐4, which renders effector T cells resistant to Treg suppression of alloimmune responses. 相似文献
13.
IL‐7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade–resistant rejection 下载免费PDF全文
He Xu Victoria A. Bendersky Todd V. Brennan Jaclyn R. Espinosa Allan D. Kirk 《American journal of transplantation》2018,18(3):720-730
Kidney transplant patients treated with belatacept without depletional induction experience higher rates of acute rejection compared to patients treated with conventional immunosuppression. Costimulation blockade–resistant rejection (CoBRR) is associated with terminally differentiated T cells. Alemtuzumab induction and belatacept/sirolimus immunotherapy effectively prevent CoBRR. We hypothesized that cells in late phases of differentiation would be selectively less capable than more naive phenotypes of repopulating postdepletion, providing a potential mechanism by which lymphocyte depletion and repopulation could reduce the risk of CoBRR. Lymphocytes from 20 recipients undergoing alemtuzumab‐induced depletion and belatacept/sirolimus immunosuppression were studied longitudinally for markers of maturation (CCR7, CD45RA, CD57, PD1), recent thymic emigration (CD31), and the IL‐7 receptor‐α (IL‐7Rα). Serum was analyzed for IL‐7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL‐7Rα+CD57?PD1? cells progressively became the predominant subset. This did not occur in a comparator group of 10 patients treated with conventional immunosuppression. Serum from depleted patients showed markedly elevated IL‐7 levels posttransplantation. Sorted CD57?PD1? cells demonstrated robust proliferation in response to IL‐7, whereas more differentiated cells proliferated poorly. These data suggest that differences in IL‐7‐dependent proliferation is one exploitable mechanism that distinguishes CoB‐sensitive and CoB‐resistant T cell populations to reduce the risk of CoBRR. (ClinicalTrials.gov ‐ NCT00565773.) 相似文献
14.
Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts 下载免费PDF全文
Cornelia Fabritius Paul Viktor Ritschl Thomas Resch Mario Roth Susanne Ebner Julia Günther Vanessa Mellitzer Anh‐Vu Nguyen Johann Pratschke Martina Sauter Karin Klingel Katja Kotsch 《American journal of transplantation》2017,17(12):3199-3209
It has already been shown that neutralization of the activating NK cell receptor NKG2D in combination with co‐stimulation blockade prolongs graft survival of vascularized transplants. In order to clarify the underlying cellular mechanisms, we transplanted complete MHC‐disparate BALB/c‐derived cardiac grafts into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1?/?). Although median survival was 8 days for both recipient groups, we detected already at day 5 posttransplantation significantly greater intragraft frequencies of NKp46+ NK cells in Klrk1?/? recipients than in wildtypes. This was followed by a significantly greater infiltration of CD4+, but a lesser infiltration of CD8+ T cell frequencies. Contrary to published observations, co‐stimulation blockade with CTLA4‐Ig resulted in a significant acceleration of cardiac rejection by Klrk1?/? recipients, and this result was confirmed by applying a neutralizing antibody against NKG2D to wildtypes. In both experimental setups, grafts derived from Klrk1?/? recipients were characterized by significantly higher levels of interferon‐γ mRNA, and both CD4+ and CD8+ T cells displayed a greater capacity for degranulation and interferon‐γ production. In summary, our results clearly illustrate that NKG2D expression in the recipient is important for cardiac allograft survival, thus supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance. 相似文献
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16.
Johannes Wedel Sarah Bruneau Kaifeng Liu Sek Won Kong Peter T. Sage David M. Sabatini Mathieu Laplante David M. Briscoe 《American journal of transplantation》2019,19(1):77-88
DEPTOR is an evolutionarily conserved cell‐intrinsic binding partner of mTOR that functions as a negative regulator of signaling responses. In this study, we show that DEPTOR is expressed within CD4+ T cells, and we observed that its relative level of expression modulates differentiation as well as glucose utilization within CD4+ T effectors in vitro. Using knock‐in mice, we also find that induced expression of DEPTOR within CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, and increases survival and suppressive function. In vivo, fully MHC mismatched cardiac allograft survival is significantly prolonged in knock‐in recipients and sustained recipient expression of DEPTOR in combination with costimulatory blockade induces long‐term graft survival. Furthermore, we show that the induced expression of DEPTOR in CD4+ T effectors fails to inhibit acute allograft rejection. Rather, prolonged survival is dominantly mediated via induced expression and function of DEPTOR within recipient CD4+ T regulatory cells. These collective findings identify DEPTOR as a novel protein that functions in CD4+ T cells to augment immunoregulation in vitro and in vivo. 相似文献
17.
Steven C. Kim David V. Mathews Cynthia P. Breeden Laura B. Higginbotham Joseph Ladowski Gregory Martens Allison Stephenson Alton B. Farris Elizabeth A. Strobert Joe Jenkins Eric M. Walters Christian P. Larsen Matthew Tector Alfred J. Tector Andrew B. Adams 《American journal of transplantation》2019,19(8):2174-2185
The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti‐pig antibodies significantly improved survival in a pig‐to–rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan–T cell depletion and an anti‐CD154–based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long‐term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti‐pig antibody and CD4 depletion resulted in consistent, long‐term xenograft survival. 相似文献
18.
Lymphoablation is routinely used in transplantation, and its success is defined by the balance of pathogenic versus protective T cells within reconstituted repertoire. While homeostatic proliferation and thymopoiesis may both cause T cell recovery during lymphopenia, the relative contributions of these mechanisms remain unclear. The goal of this study was to investigate the role of the thymus during T cell reconstitution in adult allograft recipients subjected to lymphoablative induction therapy. Compared with euthymic mice, thymectomized heart allograft recipients demonstrated severely impaired CD4 and CD8 T cell recovery and prolonged heart allograft survival after lymphoablation with murine anti‐thymocyte globulin (mATG). The injection with agonistic anti‐CD40 mAb or thymus transplantation only partially restored T cell reconstitution in mATG‐treated thymectomized mice. After mATG depletion, residual CD4 T cells migrated into the thymus and enhanced thymopoiesis. Conversely, depletion of CD4 T cells before lymphoablation inhibited thymopoiesis at the stage of CD4?CD8?CD44hiCD25+ immature thymocytes. This is the first demonstration that the thymus and peripheral CD4 T cells cooperate to ensure optimal T cell reconstitution after lymphoablation. Targeting thymopoiesis through manipulating functions of depletion‐resistant helper T cells may thus improve therapeutic benefits and minimize the risks of lymphoablation in clinical settings. 相似文献
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20.
The Impact of c‐Fos/Activator Protein‐1 Inhibition on Allogeneic Pancreatic Islet Transplantation 下载免费PDF全文
T. Yoshida M. Watanabe Y. Koshizuka D. Kuraya M. Ogura Y. Asahi H. Ono S. Emoto T. Mizukami N. Kobayashi S. Shibasaki U. Tomaru H. Kamachi M. Matsushita S. Shiozawa S. Hirono S. Todo 《American journal of transplantation》2015,15(10):2565-2575