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4-1BB Ligand

The Experts below are selected from a list of 777 Experts worldwide ranked by ideXlab platform

Byoung S. Kwon – 1st expert on this subject based on the ideXlab platform

  • Role of endogenous 4-1BB in the development of systemic lupus
    , 2020
    Co-Authors: Dass S. Vinay, Jae H. Choi, Beom K. Choi, Byoung S. Kwon

    Abstract:

    Summary Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-Fas lpr (lpr) mice deficient in 4-1BB (lpr/41BB ‐/‐‐ ) were generated and their disease phenotype was compared to that of control lpr mice. The main finding of this study is that the lpr/41BB ‐/‐‐ mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control lpr mice. The increased severity of lesions in lpr/4-1BB ‐/‐‐ mice was closely associated with increases in CD4 + T, CD3 + B220 + double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB)4-1BB Ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to lpr mice, leading to accelerated induction of disease and early mortality.

  • factor receptor superfamily, with the high-affinity IgE receptor Costimulation of mast cells by 4-1BB, a member of the tumor necrosis
    , 2020
    Co-Authors: Yuko Kawakami, Byoung S. Kwon, Michael Croft, Robert S. Mittler, Carl F. Ware, Hong Hong, Toshiaki Hajime Nishimoto, Mari Maeda-yamamoto

    Abstract:

    Abstract Mast cells are the major effector cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels upon stimulation through the high-affinity receptor for IgE (FceRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FceRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production upon FceRI stimulation. Analysis of 4-1BB Ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca 2+ flux induced by FceRI stimulation. The defective Ca 2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-γ2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FceRI-inducible 4-1BB plays a costimulatory function together with FceRI stimulation.From bloodjournal.hematologylibrary.org by guest on June 12, 2013. For personal use only.

  • 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy.
    Journal of Biochemistry and Molecular Biology, 2014
    Co-Authors: Dass S. Vinay, Byoung S. Kwon

    Abstract:

    Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural Ligand 4-1BB Ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In-depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions. [BMB Reports 2014; 47(3): 122-129]

Robert S. Mittler – 2nd expert on this subject based on the ideXlab platform

  • factor receptor superfamily, with the high-affinity IgE receptor Costimulation of mast cells by 4-1BB, a member of the tumor necrosis
    , 2020
    Co-Authors: Yuko Kawakami, Byoung S. Kwon, Michael Croft, Robert S. Mittler, Carl F. Ware, Hong Hong, Toshiaki Hajime Nishimoto, Mari Maeda-yamamoto

    Abstract:

    Abstract Mast cells are the major effector cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels upon stimulation through the high-affinity receptor for IgE (FceRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FceRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production upon FceRI stimulation. Analysis of 4-1BB Ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca 2+ flux induced by FceRI stimulation. The defective Ca 2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-γ2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FceRI-inducible 4-1BB plays a costimulatory function together with FceRI stimulation.From bloodjournal.hematologylibrary.org by guest on June 12, 2013. For personal use only.

  • Regulation of T Cell-Dependent Humoral Immunity Through CD137(4-1BB) Mediated Signals
    CD137 Pathway: Immunology and Diseases, 2020
    Co-Authors: Robert S. Mittler, Becker Hewes, Juergen Foell

    Abstract:

    CD137 (4-1BB), a member of the tumor necrosis factor receptor (TNFR) superfamily is an activation-inducible type I transmembrane protein receptor expressed on activated T cells, Natural Killer cells (NK), macrophages (Mφ), and dendritic cells (DC). Its Ligand, 4-1BB-L, is a member of the tumor necrosis factor (TNF) superfamily a type II transmembrane protein that is expressed on antigen presenting cells (APC). Ligand-induced trimerization of CD137 activates multiple signaling pathways in T cells that result in transcriptional activation, enhanced T cell activation and survival. Agonistic anti-CD137 mAbs can replace the need for 4-1BB Ligand-mediated receptor crosslinking either in vitro or in vivo. 4-1BB-L specific mAbs can drive cytokine production in APCs; anti-4-1BB Ligand mAbs that can block receptor-Ligand binding also prevent CD137-mediated T cell costimulation. However, unlike agonistic mAbs to other T cell costimulatory receptors, signaling by anti-CD137 specific mAbs can also suppress the T cellmediated immune responses. CD137 receptor-proximal and downstream signals in T cells have been largely elucidated. However, this is not the case for anti-CD137induced immune suppression. Given that NK cells and dendritic cells express this receptor, it is not clear whether T cells are the cell targets during anti-CD137 mAb induced immune suppression. In this review we discuss CD137-mediated immune suppression and its role in regulating T-dependent B cell responses and to some extent APC function in normal, autoimmune, and tumor bearing mice.

  • Anti-CD137 antibodies in the treatment of autoimmune disease and cancer.
    Immunologic research, 2020
    Co-Authors: Robert S. Mittler, Juergen Foell, Megan Mccausland, Simona Strahotin, Abhijit Bapat, L Becker Hewes

    Abstract:

    CD137 (4-1BB), is an inducible T-cell costimulatory receptor and a member of the tumor necrosis factor receptor (TNFR) superfamily. It is expressed on activated T cells and activated natural killer (NK) cells, but is constitutively expressed on a population of splenic dendritic cells (DCs). The natural counter receptor for CD137 is 4-1BB Ligand, a member of the TNF superfamily that is weakly expressed on naïve or resting B cells, macrophages, and DCs. Upon activation, the level of 4-1BBL expression increases on these cells. In T cells CD137-induced signals lead to the recruitment of TRAF family members and activation of several kinases, including ASK-1, MKK, MAPK3/ MAPK4, p38, and JNK/SAPK. Kinase activation is then followed by the activation and nuclear translocation of several transcription factors, including ATF-2, Jun, and NF-kappaB. CD137-mediated T-cell costimulation as measured by enhanced proliferation and cytokine production can be induced by anti-CD137 monoclonal antibodies (MAbs) or by employing immobilized 4-1BB Ligand. In addition to augmenting suboptimal TCR-induced proliferation, CD137-mediated signaling protects T cells, and in particular, CD8+ T cells from activation-induced cell death (AICD). Although studies with CD137-deficient or 4-1BBL-deficient mice failed to demonstrate any loss of essential immunological function, or other noteworthy deficits, we have found that 4-1BBL-deficient mice failed to generate a strong antiviral immune response following lymphocytic choriomeningitis virus (LCMV) peptide vaccination. We further found that although compromised, the immune response to LCMV vaccination in these mice could be fully restored by injecting them with anti-CD137 MAbs at the time of vaccination. Finally, we have found that injecting normal mice with anti-CD137 MAbs had profound effects on their ability to develop immune responses to allo- and autoantigens. The results of these studies discussed in this article provide a rationale for assessing the potential use of anti-CD137 MAbs for therapeutic purposes.

P A Kiener – 3rd expert on this subject based on the ideXlab platform

  • Serum levels of sCD137 (4-1BB) Ligand are prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin’s lymphoma
    European Journal of Haematology, 2006
    Co-Authors: N. Hentschel, P A Kiener, Helmut R. Salih, Matthias Krusch, Hans-jochem Kolb, Helga Schmetzer

    Abstract:

    :  CD178 (Fas/APO-1 Ligand) and CD137 Ligand (CD137L) have previously been described in sera of patients with various malignancies and play an important role in the pathogenesis of various diseases. Recently, we demonstrated that low levels of soluble (s) CD137L and high levels of sCD178 correlate significantly with a long progression free survival in patients with myelodysplastic syndrome (MDS). In this study, we correlated sCD137L and sCD178 levels in sera of 42 samples of patients with acute myeloid leukemia (AML) and 46 samples of patients with non-Hodgkin’s lymphoma (NHL) with stages, subtypes, and the clinical course of the diseases and determined cut-off values with maximum probability for significant differentiation between cases with higher/lower probability for progress free survival. In contrast to patients with MDS, surprisingly no correlation between sCD178 levels and different subtypes and stages or with prognosis in AML or NHL were observed. Regarding sCD137L, NHL-patients displayed lower levels compared with AML. Statistically significant higher median levels of sCD137L are present in patients with undifferentiated AML (M1/M2, 1470 pg/mL), poor cytogenetic risk (288 pg/mL) and higher levels of BM-blasts (186 pg/mL) compared with patients with monocytoid AML (M4/M5, 89 pg/mL), intermediate cytogenetic risk (59 pg/mL) and lower levels of BM-blasts (14 pg/mL) respectively. Furthermore, in AML patients sCD137L levels correlate significantly with the probabilities to achieve complete remission (CR), stay in CR or with progress of the disease. Taken together, our data demonstrate that sCD137L can be used as a prognostic factor not only in MDS but also in AML.

  • 4-1 BB Ligand–just another costimulating molecule?
    International journal of clinical pharmacology and therapeutics, 2002
    Co-Authors: H. R. Salih, P A Kiener, V. Nüssler

    Abstract:

    Initially, scientific interest in the 4-1BB/4-1BB Ligand system focused on the role of the 4-1 BB (CD 137) receptor in the costimulation of T cells. More recently, evidence is accumulating that 4-1BBL is more than just the Ligand for a costimulatory molecule. In this review we discuss the functional properties of 4-1BB Ligand such as its preference for CD8 positive T cells and the differences to costimulation via the B7/CD28 system. Furthermore, the available data regarding its ability to transduce signals bidirectionally, i.e. also back into the Ligand bearing cell, its release as a soluble form following shedding from the cell surface, and its role in the interaction of tumor cells with the immune system are reviewed.

  • Soluble CD137 (4-1BB) Ligand Is Released Following Leukocyte Activation and Is Found in Sera of Patients with Hematological Malignancies
    Journal of Immunology, 2001
    Co-Authors: Helmut R. Salih, G. C. Starling, Helga Schmetzer, Christine Burke, Robert Dunn, R. Pelka-fleischer, Volkmar Nuessler, P A Kiener

    Abstract:

    Expression of CD137 Ligand (4-1BBL), a member of the TNF family of proteins, has been reported on several types of APCs, various carcinoma cells, and can be induced on activated T cells. In this study, we report that the soluble Ligand was released constitutively at low levels from leukocytes and at higher levels following cellular activation. Release from cells was blocked by addition of a metalloproteinase inhibitor which concomitantly caused the accumulation of 4-1BBL on the cell surface. In addition, we show that a soluble form of 4-1BBL was present at high levels in the sera of some patients with various hematological diseases, but only at low levels in healthy donors. Soluble 4-1BBL was active in that it competed with recombinant 4-1BBL for binding to the 4-1BB receptor and was able to costimulate IL-2 and IFN-γ release from peripheral T cells. These results indicate that the release of soluble 4-1BBL from the cell surface is mediated by one or more sheddases and likely regulates 4-1BB4-1BBL interactions between cells in vivo. Cleavage of 4-1BBL to an active soluble form would alter both proximal and distal cellular responses, including cell survival and costimulatory or inflammatory responses, that are mediated through the 4-1BB pathway. This, in turn, would likely alter disease progression or outcome.