{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:56:08Z","timestamp":1790283368889,"version":"4.1.0"},"reference-count":124,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Systematic Background\/Objectives: Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which pancreatic \u03b2-cells are selectively destroyed, predominantly by autoreactive T lymphocytes. Despite decades of research, the achievement of durable immune tolerance remains elusive. This review presents a historically grounded and forward-looking perspective on the evolution of immunotherapy in T1DM, from early immunosuppressive interventions to advanced precision-based cellular approaches. Specifically, we focus on systemic immunosuppressants (e.g., corticosteroids, cyclosporine), monoclonal antibodies (e.g., anti-CD3, anti-IL-1, anti-TNF), regulatory cell-based approaches (e.g., Tregs, CAR-Tregs, MDSCs), and \u03b2-cell replacement strategies using stem cell-derived islets. Methods: We analyzed major clinical and translational milestones in immunotherapy for T1DM, with particular attention to the transition from broad immunosuppression to targeted modulation of immune pathways. Emerging data on cell-based therapies, artificial intelligence (AI)-driven stratification, and personalized intervention timing have been incorporated to provide a comprehensive overview of current and future directions. Results: Initial therapies such as corticosteroids and cyclosporine offered proof-of-concept for immune modulation, yet suffered from relapse and toxicity. The introduction of monoclonal antibodies (e.g., teplizumab) marked a shift toward immune-specific intervention, particularly in stage 2 preclinical T1DM. More recent approaches include low-dose IL-2, checkpoint modulation, and antigen-specific tolerance strategies. Cellular therapies such as Treg adoptive transfer, chimeric antigen receptor Tregs (CAR-Tregs), and stem cell-derived islet replacements (e.g., VX-880) have shown promise in preserving \u03b2-cell function and modulating autoimmunity. Myeloid-derived suppressor cells (MDSCs), although still preclinical, represent a complementary avenue for immune tolerance induction. Concurrently, AI-based models are emerging as tools to stratify risk and personalize immunotherapeutic timing, enhancing trial design and outcome prediction. Conclusions: In conclusion, the historical progression from broad immunosuppression to precision-driven strategies underscores the importance of stage-specific, mechanism-based interventions in T1DM. The convergence of targeted biologics, regenerative cell therapies, and \u03b2-cell replacement approaches, supported by AI-enabled patient stratification, offers a realistic path toward durable immune tolerance and functional \u03b2-cell preservation. Continued integration of these modalities, coupled with rigorous long-term evaluation, will be essential to transform these scientific advances into sustained clinical benefit.<\/jats:p>","DOI":"10.3390\/jcm14165621","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T13:20:09Z","timestamp":1754659209000},"page":"5621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Historically Based Perspective on the Immunotherapy of Type 1 Diabetes: Where We Have Been, Where We Are, and Where We May Go"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5438-1123","authenticated-orcid":false,"given":"Eugenio","family":"Cavalli","sequence":"first","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Rosario Pietro","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-8462","authenticated-orcid":false,"given":"Ferdinando","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1007\/s00125-021-05565-6","article-title":"Interactions between islets and regulatory immune cells in health and type 1 diabetes","volume":"64","author":"Budd","year":"2021","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1007\/s00125-002-0879-5","article-title":"Serum concentrations of the interferon-\u03b3-inducible chemokine IP-10\/CXCL10 are augmented in both newly diagnosed type I diabetes mellitus patients and subjects at risk of developing the disease","volume":"45","author":"Nicoletti","year":"2002","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s001250051619","article-title":"Serum levels of the interferon-\u03b3-inducing cytokine interleukin-18 are increased in individuals at high risk of developing Type I diabetes","volume":"44","author":"Nicoletti","year":"2001","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cavalli, E., Rosario, G., Nicoletti, P., and Nicoletti, F. 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