{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:41:42Z","timestamp":1777480902792,"version":"3.51.4"},"reference-count":75,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"JST START University Ecosystem Promotion Type (Supporting the Creation of Startup Ecosystems in Startup Cities), Japan","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Grants-in-Aid for Scientific Research from MEXT","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Grants-in-Aid for Scientific Research from MEXT","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Grants-in-Aid for Scientific Research from MEXT","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Grants-in-Aid for Scientific Research from MEXT","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Grants-in-Aid for Scientific Research from MEXT","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Grants-in-Aid for Scientific Research from the Japan Agency for Medical Research and Development","award":["A90"],"award-info":[{"award-number":["A90"]}]},{"name":"Research Funding granted by Nagasaki University President Shigeru Kohno","award":["JPMJST2281"],"award-info":[{"award-number":["JPMJST2281"]}]},{"name":"Research Funding granted by Nagasaki University President Shigeru Kohno","award":["16K08844"],"award-info":[{"award-number":["16K08844"]}]},{"name":"Research Funding granted by Nagasaki University President Shigeru Kohno","award":["23K06677"],"award-info":[{"award-number":["23K06677"]}]},{"name":"Research Funding granted by Nagasaki University President Shigeru Kohno","award":["A48"],"award-info":[{"award-number":["A48"]}]},{"name":"Research Funding granted by Nagasaki University President Shigeru Kohno","award":["A90"],"award-info":[{"award-number":["A90"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>\u03b3\u03b4 T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, \u03b3\u03b4 T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia\u2013lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing \u03b3\u03b4 T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2\/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2\/IL-18 for 11 days to expand \u03b3\u03b4 T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2\/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of \u03b3\u03b4 T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the \u03b3\u03b4 T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that \u03b3\u03b4 T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the \u03b3\u03b4 T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of \u03b3\u03b4 T cells and NK cells expanded with PTA\/IL-2\/IL-18 is a promising alternative therapy for ATL.<\/jats:p>","DOI":"10.3390\/cells13020128","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T05:47:21Z","timestamp":1704865641000},"page":"128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Development of Innate-Immune-Cell-Based Immunotherapy for Adult T-Cell Leukemia\u2013Lymphoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Maho","family":"Nakashima","sequence":"first","affiliation":[{"name":"Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5024-0614","authenticated-orcid":false,"given":"Yoshimasa","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Medical Innovation, Nagasaki University, Nagasaki 852-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruki","family":"Okamura","sequence":"additional","affiliation":[{"name":"Department of Tumor Cell Therapy, Hyogo College of Medicine, Nishinomiya 663-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeharu","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nagasaki University Hospital, Nagasaki 852-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitaka","family":"Imaizumi","sequence":"additional","affiliation":[{"name":"Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura 856-8562, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, National Hospital Organization Nagasaki Medical Center, Omura 856-8562, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Murota","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan"},{"name":"Leading Medical Research Core Unit, Life Science Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1182\/blood.V50.3.481.481","article-title":"Adult T-cell leukemia: Clinical and hematologic features of 16 cases","volume":"50","author":"Uchiyama","year":"1977","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1742-4690-2-16","article-title":"Discovery of adult T-cell leukemia","volume":"2","author":"Takatsuki","year":"2005","journal-title":"Retrovirology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gessain, A., and Cassar, O. 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