{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T23:02:49Z","timestamp":1787353369912,"version":"build-2736575974"},"reference-count":84,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T00:00:00Z","timestamp":1739664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In vitro models serve as valuable tools for understanding the complex cellular and molecular interactions involved in granuloma formation, providing a controlled environment to explore the underlying mechanisms of their development and function. Various models have been developed to replicate granulomatous diseases, even though they may lack the sophistication needed to fully capture the variability present in clinical spectra and environmental influences. Traditional cultures of PBMCs have been widely used to generate granuloma models, enabling the study of aggregation responses to various stimuli. However, growing cells on a two-dimensional (2D) plastic surface as a monolayer can lead to altered cellular responses and the modulation of signaling pathways, which may not accurately represent in vivo conditions. In response to these limitations, the past decade has seen significant advancements in the development of three-dimensional (3D) in vitro models, which more effectively mimic in vivo conditions and provide better insights into cell\u2013cell and cell\u2013microenvironment interactions. Meanwhile, the use of in vivo animal models in biomedical research must adhere to the principle of the three Rs (replacement, reduction, and refinement) while ensuring that the models faithfully replicate human-specific processes. This review summarizes and compares the main models developed to investigate granulomas, focusing on their contribution to advancing our understanding of granuloma biology. We also discuss the strengths and limitations of each model, offering insights into their biological relevance and practical applications.<\/jats:p>","DOI":"10.3390\/cells14040293","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T07:48:22Z","timestamp":1739778502000},"page":"293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Shaping Rare Granulomatous Diseases in the Lab: How New Models Are Changing the Game"],"prefix":"10.3390","volume":"14","author":[{"given":"Jessica","family":"Ceccato","sequence":"first","affiliation":[{"name":"Hematology and Clinical Immunology Unit, Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM), 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4160-0091","authenticated-orcid":false,"given":"Giulia","family":"Gualtiero","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Unit, Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM), 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6640-5401","authenticated-orcid":false,"given":"Maria","family":"Piazza","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7373-9695","authenticated-orcid":false,"given":"Samuela","family":"Carraro","sequence":"additional","affiliation":[{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Buso","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Felice","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rattazzi","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1085-2333","authenticated-orcid":false,"given":"Riccardo","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7174-4651","authenticated-orcid":false,"given":"Fabrizio","family":"Vianello","sequence":"additional","affiliation":[{"name":"Hematology and Clinical Immunology Unit, Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM), 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8486-5850","authenticated-orcid":false,"given":"Francesco","family":"Cinetto","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"},{"name":"Rare Diseases Referral Center, Internal Medicine 1, Ca\u2019 Foncello Hospital, AULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s12016-015-8481-z","article-title":"Etiologies of Sarcoidosis","volume":"49","author":"Chen","year":"2015","journal-title":"Clin. 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