{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:44:09Z","timestamp":1790117049898,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2021\/05494-8"],"award-info":[{"award-number":["2021\/05494-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2023\/08509-1"],"award-info":[{"award-number":["2023\/08509-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2021\/05494-8"],"award-info":[{"award-number":["2021\/05494-8"]}],"id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2023\/08509-1"],"award-info":[{"award-number":["2023\/08509-1"]}],"id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Sporotrichosis is an emerging zoonotic subcutaneous fungal infection with limited therapeutic options, highlighting the need for improved immunomodulatory strategies. CTLA-4 is an inhibitory immune checkpoint that negatively regulates T-cell activation. In this study, we evaluated whether a CTLA-4 antisense oligonucleotide (CTLA-4 ASO) is associated with enhanced immune responses to an adjuvanted recombinant Sporothrix sp. enolase antigen (rSsEno) formulation. Methods: CTLA-4 ASO uptake, cytotoxicity, and gene-silencing activity were assessed in murine splenocytes in vitro. BALB\/c mice were immunized with rSsEno formulated with Montanide Gel 01, either alone or in combination with 5 \u00b5g CTLA-4 ASO. Antigen-specific serum antibody responses were quantified by ELISA. Splenocytes from immunized mice were restimulated with enolase, and cytokine production (IFN-\u03b3, IL-2, IL-17, and TNF-\u03b1) was measured using Cytometric Bead Array (CBA). Results: CTLA-4 ASO was efficiently internalized by splenocytes and was associated with reduced expression of CTLA-4 without detectable cytotoxicity in vitro. Mice receiving the ASO-supplemented formulation developed significantly higher anti-enolase antibody titers compared to those immunized with adjuvant alone. Upon antigen restimulation, splenocytes from ASO-treated mice produced higher levels of IFN-\u03b3, IL-2, TNF-\u03b1, and IL-17, consistent with an enhanced recall response characterized by a mixed Th1\/Th17 cytokine profile. Conclusions: CTLA-4 ASO was associated with an enhanced recall response characterized by a mixed Th1\/Th17 cytokine profile. These findings suggest a potential immunomodulatory effect of CTLA-4 targeting. Further studies incorporating dose optimization, infection challenge models, and appropriate sequence controls are required to determine the specificity and relevance of these effects for protective immunity against sporotrichosis.<\/jats:p>","DOI":"10.3390\/vaccines14040334","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:21:32Z","timestamp":1775737292000},"page":"334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CTLA-4 Antisense Oligonucleotide Contributes to Enhanced Immunogenicity of an Adjuvanted Recombinant Sporothrix spp. Enolase Antigen"],"prefix":"10.3390","volume":"14","author":[{"given":"Giovanna Justino","family":"Momente","sequence":"first","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2678-0431","authenticated-orcid":false,"given":"Deivys Leandro","family":"Portuondo","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8185-4299","authenticated-orcid":false,"given":"Adriana Fernandes de","family":"Deus","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus Ricardo","family":"Curti Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3958-3218","authenticated-orcid":false,"given":"Fernanda Luiza","family":"Piccineli","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarcila Pavicic Catalan","family":"de Oliveira Campos","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiana","family":"T\u00e9llez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0084-3468","authenticated-orcid":false,"given":"Iracilda Zeppone","family":"Carlos","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1875-0518","authenticated-orcid":false,"given":"Alexander","family":"Batista-Duharte","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"},{"name":"Department of Cell Biology, Physiology and Immunology, University of Cordoba, Av. Menendez Pidal s\/n, 14004 Cordoba, Spain"},{"name":"Immunology and Allergy Group (GC01), Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, 14004 Cordoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/blood-2017-06-741033","article-title":"CTLA-4: A moving target in immunotherapy","volume":"131","author":"Rowshanravan","year":"2018","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hossen, M.M., Ma, Y., Yin, Z., Xia, Y., Du, J., Huang, J.Y., Huang, J.J., Zou, L., Ye, Z., and Huang, Z. (2023). Current understanding of CTLA-4: From mechanism to autoimmune diseases. Front. 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