Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance

Wells, Andrew D.; Li, Xian Chang; Li, Yongsheng; Walsh, Matthew C.; Zheng, Xin Xiao; Wu, Zihao; Núñez, Gabriel; Tang, Aimin; Sayegh, Mohamed H.; Hancock, Wayne W.; Strom, Terry B.; Turka, Laurence A.

doi:10.1038/15260

Cited by 571 publications

(453 citation statements)

References 24 publications

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“…Recent studies show that IFN-c and IL-2 promote allograft acceptance in vivo (Konieczny et al 1998;Wells et al 1999). Accordingly, our data showed higher levels of IL-2 and IFN-c in the group without GVHD compared to the GVHD group.…”

Section: Cytokine Release and Significance Of Cytokines In Clinical Tsupporting

confidence: 68%

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

Fischbacher¹,

Merle²,

Liepert³

et al. 2015

Cell Communication & Adhesion

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To enlighten interactions between autologous, allogeneic or T-cells from patients after stem cell transplantation with leukaemia-derived-dendritic-cells containing dendritic cells or blast containing mononuclear cells (n ¼ 21, respectively), we determined cytokine-concentrations (interleukin 2, 4, 6, 10, tumor-necrosis-factor-a, interferon-c) in supernatants of mixed-lymphocyte-culture and in serum (n ¼ 16) of 20 patients with acute myeloid leukaemia and three patients with myelodysplastic syndromes by cytometric-bead-assay. We correlated our data with lytic capabilities of stimulated T-cells in a fluorolysis-assay and clinical data: Dendritic-cell-/mononuclear-cell-stimulation of T-cells resulted in increased cytokine-levels in culture-medium compared to serum. There were no significant differences between cytokine-patterns of cases with/without lytic T-cell-activity, response to immunotherapy (stem cell transplantation/donor-lymphocyte-infusion) or graft-versus-host-disease. However, some predictive cytokine-cut-off-values for antileukaemic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease could be defined. Cytokine-profiles alone, without functional assays, are no useful tool to predict antileukaemic T-cell-function, although they can indicate lytic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease. ARTICLE HISTORY

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Section: Cytokine Release and Significance Of Cytokines In Clinical Tsupporting

confidence: 68%

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

Fischbacher¹,

Merle²,

Liepert³

et al. 2015

Cell Communication & Adhesion

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“…These drugs, however, prevent up-regulation of CD95L after T cell activation and therefore inhibit AICD. In contrast RAP does not block AICD [26].…”

Section: Introductionmentioning

confidence: 74%

“…The importance of apoptosis induction for peripheral transplantation tolerance has been demonstrated in recent reports [26,49]. Wells et al showed that mice transgenic for bcl-x L expression in T cells or IL-2 deficient mice are resistant to the induction of transplantation tolerance due to defective passive or active T cell apoptosis pathways.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

149

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SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.

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“…Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia.…”

Section: Introductionmentioning

confidence: 99%

Homeostatic proliferation is a barrier to transplantation tolerance

Bensinger

Zhang

et al. 2003

Nat Med

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384

362

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Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells 1,2 . Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation 7,8 , may induce acquisition of functional memory T cells 9-13 . Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.T cells undergo homeostatic proliferation when transferred into severe combined immunodeficiency (scid), recombination-activating gene-deficient or irradiated recipients7 ,8 . In many clinical transplantation protocols, T-cell depletion is less profound. We therefore asked whether residual nondepleted cells could undergo homeostatic proliferation. We treated mice with two doses (100 μg/dose) of depleting monoclonal antibodies directed at CD4 and CD8 (days 0 and 5). This induced 80-90% T-cell depletion, which was maintained for >10 d after the last dose (data not shown).

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Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance

Cited by 571 publications

References 24 publications

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Homeostatic proliferation is a barrier to transplantation tolerance

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