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81.
Neujahr DC Chen C Huang X Markmann JF Cobbold S Waldmann H Sayegh MH Hancock WW Turka LA 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(8):4632-4639
Partial T cell depletion is used in solid organ transplantation as a valuable strategy of peritransplant induction immunosuppression. Using a murine cardiac allograft model, we recently demonstrated that this led to lymphopenia-induced (homeostatic) proliferation among the residual nondepleted lymphocytes. Rather than promoting tolerance, peritransplant T cell-depleting Abs actually resulted in resistance to tolerance induction by costimulatory blockade. In this study we show that memory T cells predominate shortly after subtotal lymphodepletion due to two distinct mechanisms: relative resistance to depletion and enhanced homeostatic proliferation. In contrast, regulatory cells (CD4+ CD25+ Foxp3+) are depleted as efficiently as nonregulatory cells and exhibit reduced homeostatic expansion compared with memory cells. The resistance to tolerance induction seen with subtotal T cell depletion can be overcome in two different ways: first, by the adoptive transfer of additional unprimed regulatory cells at the time of transplant, and second, by the adjunctive use of nondepleting anti-CD4 and anti-CD8 mAbs, which effectively block homeostatic expansion. We conclude that the resistance to tolerance induction seen after subtotal lymphocyte depletion can be attributed to alterations in the balance of naive, memory, and regulatory T cells. These data have clinically relevant implications related to the development of novel strategies to overcome resistance to tolerance. 相似文献
82.
83.
Sylvaine You Lynn Poulton Steve Cobbold Chih-Pin Liu Michael Rosenzweig Douglas Ringler Wen-Hui Lee Berta Segovia Jean-Fran?ois Bach Herman Waldmann Lucienne Chatenoud 《PloS one》2009,4(11)
Background
The cross-talk between pathogenic T lymphocytes and regulatory T cells (Tregs) plays a major role in the progression of autoimmune diseases. Our objective is to identify molecules and/or pathways involved in this interaction and representing potential targets for innovative therapies. Glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand are key players in the T effector/Treg interaction. GITR is expressed at low levels on resting T cells and is significantly up-regulated upon activation. Constitutive high expression of GITR is detected only on Tregs. GITR interacts with its ligand mainly expressed on antigen presenting cells and endothelial cells. It has been suggested that GITR triggering activates effector T lymphocytes while inhibiting Tregs thus contributing to the amplification of immune responses. In this study, we examined the role of GITR/GITRLigand interaction in the progression of autoimmune diabetes.Methods and Findings
Treatment of 10-day-old non-obese diabetic (NOD) mice, which spontaneously develop diabetes, with an agonistic GITR-specific antibody induced a significant acceleration of disease onset (80% at 12 weeks of age). This activity was not due to a decline in the numbers or functional capacity of CD4+CD25+Foxp3+ Tregs but rather to a major activation of ‘diabetogenic’ T cells. This conclusion was supported by results showing that anti-GITR antibody exacerbates diabetes also in CD28−/− NOD mice, which lack Tregs. In addition, treatment of NOD mice, infused with the diabetogenic CD4+BDC2.5 T cell clone, with GITR-specific antibody substantially increased their migration, proliferation and activation within the pancreatic islets and draining lymph nodes. As a mirror image, blockade of the GITR/GITRLigand pathway using a neutralizing GITRLigand-specific antibody significantly protected from diabetes even at late stages of disease progression. Experiments using the BDC2.5 T cell transfer model suggested that the GITRLigand antibody acted by limiting the homing and proliferation of pathogenic T cells in pancreatic lymph nodes.Conclusion
GITR triggering plays an important costimulatory role on diabetogenic T cells contributing to the development of autoimmune responses. Therefore, blockade of the GITR/GITRLigand pathway appears as a novel promising clinically oriented strategy as GITRLigand-specific antibody applied at an advanced stage of disease progression can prevent overt diabetes. 相似文献84.
Comparison of Shiga-Toxigenic Escherichia coli Prevalences among Dairy, Feedlot, and Cow-Calf Herds in Washington State 下载免费PDF全文
Rowland N. Cobbold Daniel H. Rice Maryanne Szymanski Douglas R. Call Dale D. Hancock 《Applied microbiology》2004,70(7):4375-4378
Shiga-toxigenic Escherichia coli (STEC) strains were isolated from 7.4% of 1,440 fecal and farm environmental samples. Shiga toxin gene and STEC prevalences were significantly associated with animal production type and season. A range of serogroups were identified. Nine percent of isolates possessed all three principal virulence markers: stx2, eae, and ehx. 相似文献
85.
Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance 总被引:15,自引:0,他引:15
Graca L Honey K Adams E Cobbold SP Waldmann H 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(9):4783-4786
Nondepleting anti-CD154 (CD40 ligand) mAbs have proven effective in inducing transplantation tolerance in rodents and primates. In the induction phase, anti-CD154 Ab therapy is known to enhance apoptosis of Ag reactive T cells. However, this may not be the sole explanation for tolerance, as we show in this study that tolerance is maintained through a dominant regulatory mechanism which, like tolerance induced with CD4 Abs, manifests as infectious tolerance. Therefore, tolerance induced with anti-CD154 Abs involves not only the deletion of potentially aggressive T cells, but also a contagious spread of tolerance to new cohorts of graft-reactive T cells as they arise. 相似文献
86.
Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants 总被引:25,自引:0,他引:25
Cobbold SP Castejon R Adams E Zelenika D Graca L Humm S Waldmann H 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(10):6003-6010
Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts. 相似文献
87.
Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance 总被引:18,自引:0,他引:18
Graca L Thompson S Lin CY Adams E Cobbold SP Waldmann H 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(11):5558-5565
CD4(+)CD25(+) T cells have been proposed as the principal regulators of both self-tolerance and transplantation tolerance. Although CD4(+)CD25(+) T cells do have a suppressive role in transplantation tolerance, so do CD4(+)CD25(-) T cells, although 10-fold less potent. Abs to CTLA-4, CD25, IL-10, and IL-4 were unable to abrogate suppression mediated by tolerant spleen cells so excluding any of these molecules as critical agents of suppression. CD4(+)CD25(+) T cells from naive mice can also prevent rejection despite the lack of any previous experience of donor alloantigens. However, this requires many more naive than tolerized cells to provide the same degree of suppression. This suggests that a capacity to regulate transplant rejection pre-exists in naive mice, and may be amplified in "tolerized" mice. Serial analysis of gene expression confirmed that cells sorted into CD4(+)CD25(+) and CD4(+)CD25(-) populations were distinct in that they responded to TCR ligation with very different programs of gene expression. Further characterization of the differentially expressed genes may lead to the development of diagnostic tests to monitor the tolerant state. 相似文献
88.
Morgan W. D. Ryde S. J. S. Jones Sarah J. Wyatt Ruth M. Hainsworth I. R. Cobbold Stephanie S. Evans C. J. Braithwaite R. A. 《Biological trace element research》1990,26(1):407-414
This paper reports the preliminary findings of a survey of lead and cadmium body burdens in a nonoccupationally exposed population in Swansea, Wales, using the techniques of in vivo neutron activation and X-ray fluorescence analysis. Some measurements on an occupationally cadmium-exposed group are also included. The results confirm the association between cadmium and smoking and bone lead and age. The in vivo measurements demonstrate a degree of comparability with other data, which supports the further detailed analysis of the relationships between body burden and exposure, on the one hand, and possible health effects on the other.
相似文献89.
Inhibitors of protein kinase C prolong the falling phase of each free-calcium transient in a hormone-stimulated hepatocyte. 总被引:1,自引:0,他引:1 下载免费PDF全文
A Sanchez-Bueno C J Dixon N M Woods K S Cuthbertson P H Cobbold 《The Biochemical journal》1990,268(3):627-632
Many cells generate oscillations in cytoplasmic free Ca2+ concentration ('free Ca') when stimulated with Ca-mobilizing hormones. The frequency of repetitive free-Ca transients in a rat hepatocyte is a function of hormone concentration and can be depressed by phorbol esters. We show here that the protein kinase C (PKC) inhibitors staurosporine and sphingosine can reverse the effects of phorbol dibutyrate on the frequency of free-Ca transients induced by phenylephrine or vasopressin. An important feature of the hepatocyte free-Ca oscillator is that the transient's time course, particularly the rate of fall of free Ca from peak to resting, depends on the species of agonist, and is measurably different for phenylephrine, vasopressin, angiotensin II or ATP. We show here that the rate of fall of free Ca in transients induced by phenylephrine or vasopressin is markedly decreased after treatment of the cells with a PKC inhibitor. A receptor-controlled oscillator model is discussed, in which PKC provides negative feedback during the falling phase of free-Ca transients. 相似文献
90.