Synthetic imidazoquinolines potently and broadly activate the cellular immune response of patients with cutaneous T-cell lymphoma: synergy with interferon-gamma enhances production of interleukin-12
| Autor: | Joel M. Gelfand, Alain H. Rook, Stephen K. Richardson, Aidan Hancock, Sarah B. Newton, Jihed Chehimi, Maria Wysocka, Camille E. Introcaso, Bernice M. Benoit, Luis J. Montaner |
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| Rok vydání: | 2007 |
| Předmět: |
Agonist
Cancer Research Cellular immunity Skin Neoplasms medicine.drug_class T-Lymphocytes Interferon-gamma Immune system medicine Humans Sezary Syndrome Interferon gamma Immunity Cellular business.industry Cutaneous T-cell lymphoma Imidazoles Interleukin Hematology General Medicine Dendritic cell medicine.disease Interleukin-12 Lymphoma T-Cell Cutaneous Killer Cells Natural Oncology Toll-Like Receptor 7 Toll-Like Receptor 8 Immunology Interleukin 12 Quinolines business medicine.drug |
| Zdroj: | Clinical lymphomamyeloma. 7(8) |
| ISSN: | 1557-9190 |
| Popis: | Advanced cutaneous T-cell lymphoma (CTCL) is typically associated with a variety of profound defects of cellular immunity, including depressed dendritic cell numbers and function. Therefore, we investigated the ability of synthetic imidazoquinolines, which are agonists for Toll-like receptors (TLRs) 7 and 8, to enhance in vitro the cell-mediated immunity of patients with leukemic CTCL and Sezary syndrome. Patients' peripheral blood mononuclear cells (PBMCs) stimulated with the TLR7 agonist 3M-001 produced high levels of interferon (IFN)-alpha, and the TLR8 agonist 3M-002 potently induced predominantly interleukin (IL)-12 and IFN-gamma. Marked upregulation of CD69 and CD25 on natural killer (NK) cells and T cells from patients and an increase in NK cytolytic activity was also observed. We further demonstrate that priming of patients' PBMCs with IFN-gamma has the ability to synergistically enhance the production of IL-12 induced by a synthetic agonist for TLR8. The underlying mechanisms of increased IL-12 production in response to priming with IFN appears to involve an increase in IL-12 p35 and IL-12 p40 gene transcription and a decrease in IL-10 levels upon stimulation with the TLR8 agonist. Our data demonstrate the ability of imidazoquinolines to potently stimulate cellular immune responses of patients with CTCL and emphasizes the benefit of using a combination of biologic modifiers to further enhance their immune responses. |
| Databáze: | OpenAIRE |
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