Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL)
| Autor: | Helmut R. Salih, Corina Buechele, Stefan Wirths, Tina Baessler, Benjamin J Schmiedel, J U Schmohl |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_treatment Chronic lymphocytic leukemia Antineoplastic Agents Biology Ligands Antibodies Monoclonal Murine-Derived Glucocorticoid-Induced TNFR-Related Protein hemic and lymphatic diseases medicine Humans Aged Aged 80 and over Degranulation Interleukin Hematology Middle Aged Flow Cytometry medicine.disease Leukemia Lymphocytic Chronic B-Cell Killer Cells Natural Immunosurveillance Leukemia Cytokine Oncology Drug Resistance Neoplasm Immunology Cytokines Female Tumor necrosis factor alpha Rituximab |
| Zdroj: | Leukemia. 26:991-1000 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2011.313 |
| Popis: | Natural killer (NK) cells play an important role in the immunosurveillance of hematopoietic malignancies. Their reactivity is influenced by activating and inhibitory signals mediated by tumor-expressed ligands for NK receptors. Many members of the tumor necrosis factor (TNF) family modulate differentiation, proliferation, activation and death of both tumor and immune effector cells. The TNF receptor family member glucocorticoid-induced TNFR-related protein (GITR) stimulates anti-tumor immunity in mice, but available data indicate that GITR may mediate different effects in mice and men and impairs the reactivity of human NK cells. Here, we comprehensively studied the expression and function of GITR ligand (GITRL) in leukemia. Among the different leukemia entities, pronounced expression of GITRL on leukemic cells was observed in chronic lymphocytic leukemia (CLL), and the GITR receptor was expressed at significantly higher levels on NK cells of CLL patients compared with healthy controls. Upon GITR-GITRL interaction, signaling via GITRL into the leukemia cells induced the release of interleukin (IL)-6, IL-8 and TNF, which act as growth and survival factors for CLL cells. In addition, GITRL impaired both direct and Rituximab-induced degranulation, cytotoxicity and interferon-γ production of NK cells, which could be restored by GITR blocking antibodies. Thus, GITRL may contribute to disease pathophysiology and resistance to direct and Rituximab-induced NK reactivity in CLL. |
| Databáze: | OpenAIRE |
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