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Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses
A small proportion of human T-cell leukemia virus type-1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma, a chemotherapy-resistant lymphoproliferative disease with a poor prognosis. HTLV-1-specific cytotoxic T lymphocytes (CTLs), potential anti-tumor/virus effectors, are impaire...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928132/ https://www.ncbi.nlm.nih.gov/pubmed/36730466 http://dx.doi.org/10.1371/journal.ppat.1011104 |
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author | Hasegawa, Atsuhiko Murata, Megumi Fujikawa, Tomoka Katagiri, Kuniko Nagano, Yoshiko Masuda, Takao Kuramitsu, Madoka Nakajima, Shinsuke Fujisawa, Jun-ichi Okuma, Kazu Grover, Poonam Kidiga, Maureen Akari, Hirofumi Kannagi, Mari |
author_facet | Hasegawa, Atsuhiko Murata, Megumi Fujikawa, Tomoka Katagiri, Kuniko Nagano, Yoshiko Masuda, Takao Kuramitsu, Madoka Nakajima, Shinsuke Fujisawa, Jun-ichi Okuma, Kazu Grover, Poonam Kidiga, Maureen Akari, Hirofumi Kannagi, Mari |
author_sort | Hasegawa, Atsuhiko |
collection | PubMed |
description | A small proportion of human T-cell leukemia virus type-1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma, a chemotherapy-resistant lymphoproliferative disease with a poor prognosis. HTLV-1-specific cytotoxic T lymphocytes (CTLs), potential anti-tumor/virus effectors, are impaired in adult T-cell leukemia/lymphoma patients. Here, using Japanese monkeys naturally infected with simian T-cell leukemia/T-lymphotropic virus type-1 (STLV-1) as a model, we demonstrate that short-term-cultured autologous peripheral blood mononuclear cells (PBMCs) can serve as a therapeutic vaccine to activate such CTLs. In a screening test, STLV-1-specific CTL activity was detectable in 8/10 naturally STLV-1-infected monkeys. We conducted a vaccine study in the remaining two monkeys with impaired CTL responses. The short-term-cultured PBMCs of these monkeys spontaneously expressed viral antigens, in a similar way to PBMCs from human HTLV-1 carriers. The first monkey was subcutaneously inoculated with three-day-cultured and mitomycin C (MMC)-treated autologous PBMCs, and then boosted with MMC-treated autologous STLV-1-infected cell line cells. The second monkey was inoculated with autologous PBMC-vaccine alone twice. In addition, a third monkey that originally showed a weak STLV-1-specific CTL response was inoculated with similar autologous PBMC-vaccines. In all three vaccinated monkeys, marked activation of STLV-1-specific CTLs and a mild reduction in the STLV-1 proviral load were observed. Follow-up analyses on the two monkeys vaccinated with PBMCs alone indicated that STLV-1-specific CTL responses peaked at 3–4 months after vaccination, and then diminished but remained detectable for more than one year. The significant reduction in the proviral load and the control of viral expression were associated with CTL activation but also diminished 6 and 12 months after vaccination, respectively, suggesting the requirement for a booster. The vaccine-induced CTLs in these monkeys recognized epitopes in the STLV-1 Tax and/or Envelope proteins, and efficiently killed autologous STLV-1-infected cells in vitro. These findings indicated that the autologous PBMC-based vaccine could induce functional STLV-1-specific CTLs in vivo. |
format | Online Article Text |
id | pubmed-9928132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-99281322023-02-15 Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses Hasegawa, Atsuhiko Murata, Megumi Fujikawa, Tomoka Katagiri, Kuniko Nagano, Yoshiko Masuda, Takao Kuramitsu, Madoka Nakajima, Shinsuke Fujisawa, Jun-ichi Okuma, Kazu Grover, Poonam Kidiga, Maureen Akari, Hirofumi Kannagi, Mari PLoS Pathog Research Article A small proportion of human T-cell leukemia virus type-1 (HTLV-1)-infected individuals develop adult T-cell leukemia/lymphoma, a chemotherapy-resistant lymphoproliferative disease with a poor prognosis. HTLV-1-specific cytotoxic T lymphocytes (CTLs), potential anti-tumor/virus effectors, are impaired in adult T-cell leukemia/lymphoma patients. Here, using Japanese monkeys naturally infected with simian T-cell leukemia/T-lymphotropic virus type-1 (STLV-1) as a model, we demonstrate that short-term-cultured autologous peripheral blood mononuclear cells (PBMCs) can serve as a therapeutic vaccine to activate such CTLs. In a screening test, STLV-1-specific CTL activity was detectable in 8/10 naturally STLV-1-infected monkeys. We conducted a vaccine study in the remaining two monkeys with impaired CTL responses. The short-term-cultured PBMCs of these monkeys spontaneously expressed viral antigens, in a similar way to PBMCs from human HTLV-1 carriers. The first monkey was subcutaneously inoculated with three-day-cultured and mitomycin C (MMC)-treated autologous PBMCs, and then boosted with MMC-treated autologous STLV-1-infected cell line cells. The second monkey was inoculated with autologous PBMC-vaccine alone twice. In addition, a third monkey that originally showed a weak STLV-1-specific CTL response was inoculated with similar autologous PBMC-vaccines. In all three vaccinated monkeys, marked activation of STLV-1-specific CTLs and a mild reduction in the STLV-1 proviral load were observed. Follow-up analyses on the two monkeys vaccinated with PBMCs alone indicated that STLV-1-specific CTL responses peaked at 3–4 months after vaccination, and then diminished but remained detectable for more than one year. The significant reduction in the proviral load and the control of viral expression were associated with CTL activation but also diminished 6 and 12 months after vaccination, respectively, suggesting the requirement for a booster. The vaccine-induced CTLs in these monkeys recognized epitopes in the STLV-1 Tax and/or Envelope proteins, and efficiently killed autologous STLV-1-infected cells in vitro. These findings indicated that the autologous PBMC-based vaccine could induce functional STLV-1-specific CTLs in vivo. Public Library of Science 2023-02-02 /pmc/articles/PMC9928132/ /pubmed/36730466 http://dx.doi.org/10.1371/journal.ppat.1011104 Text en © 2023 Hasegawa et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hasegawa, Atsuhiko Murata, Megumi Fujikawa, Tomoka Katagiri, Kuniko Nagano, Yoshiko Masuda, Takao Kuramitsu, Madoka Nakajima, Shinsuke Fujisawa, Jun-ichi Okuma, Kazu Grover, Poonam Kidiga, Maureen Akari, Hirofumi Kannagi, Mari Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title | Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title_full | Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title_fullStr | Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title_full_unstemmed | Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title_short | Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses |
title_sort | vaccination with short-term-cultured autologous pbmcs efficiently activated stlv-1-specific ctls in naturally stlv-1-infected japanese monkeys with impaired ctl responses |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928132/ https://www.ncbi.nlm.nih.gov/pubmed/36730466 http://dx.doi.org/10.1371/journal.ppat.1011104 |
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