The expansion of CD4+CD28- T cells in patients with chronic kidney graft rejection.
ABSTRACT CD4+CD28- T cells are oligoclonal lymphocytes rarely found in healthy subjects, but are present in high frequencies in patients with inflammatory diseases. Contrary to paradigm, they are functionally active and produce interferon gamma and cytolytic proteins, are cytotoxic in vessels and may contribute to tissue damage. The size of the peripheral blood CD4+CD28- T cell compartments was determined in 20 healthy individuals, 20 patients after renal transplantation with stable graft function, and 20 with chronic graft rejection by two-color FACS analysis. In patients with stable graft function, the median frequency of CD4+CD28- T cells was 3.1% and was significantly higher in comparison to the control group (1.4%) (P <.01). The highest subset CD4+CD28- cells was detected in patients with chronic graft rejection (10.65%). The amount of CD4+CD28- cells was significantly higher in this group in comparison to patients with stable graft function (P <.01). The evaluated number of CD4+CD28- cells in patients after renal transplantation, especially in graft recipients with chronic graft rejection, suggests a role of these cells in chronic graft destruction.
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ABSTRACT: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.PLoS ONE 01/2012; 7(3):e33939. · 3.53 Impact Factor
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ABSTRACT: Chronic rejection is a poorly understood entity albeit a frequent cause of graft failure. Despite the advent of new immunosuppressive agents, neither the slope of graft destruction nor the frequency is ameliorated. There are a number of hypothesis which try to explain the conundrum of chronic graft destruction: ongoing rejection, antibody-mediated rejection, poor choice of organs, hyperfiltration, calcineurin inhibitors (CNI) nephrotoxicity and non-compliance among them. None of these hypotheses can explain all features of the process, thus, it is likely that they act in combination. What seems to be clear is a beneficial effect of early angiotensin-converting enzyme (ACE)/AT1 blocker treatment. It is less clear, however, whether a reduction or a switch from CNIs to other immunosuppressants prolongs graft survival. This review highlights the pathophysiological aspects that are important for the development of chronic allograft damage in the context of possible treatment options.Nephrology Dialysis Transplantation 04/2013; · 3.37 Impact Factor
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ABSTRACT: The presence of CD28− memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA-4Ig induction therapy. In vitro analyses have indicated poor alloantigen-induced CD28− memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28− memory CD8 T cell proliferation. Addition of IL-15, but not IL-2 or IL-7, to co-cultures of CD28− or CD28+ memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28− and enhanced CD28+ memory T cell proliferation. Proliferating CD28− memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28+ memory CD8 T cells. CTLA-4Ig inhibited alloantigen-induced proliferation of CD28+ memory CD8 T cell proliferation but had no effect on alloantigen plus IL-15-induced proliferation of either CD28− or CD28+ memory CD8 T cells. These results indicate the ability of IL-15, a cytokine produced by renal epithelial during inflammation, to provoke CD28− memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA-4Ig-mediated costimulation blockade.American Journal of Transplantation 05/2014; · 6.19 Impact Factor