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en Enhancing Immune Tolerance and Insulin Secretion of Mesenchymal Stem Cell-Derived Insulin-Producing cells via Interferon-γ and Tumor Necrosis Factor-α Priming ایمنی شناسی Immunology مقالات اصلی Original Article <div class="WordSection1" style="text-align: justify;">Background: Mesenchymal stem cells (MSCs) have the potential to treat type 1 diabetes mellitus (T1DM) by differentiating into insulin-producing cells (IPCs). However, various immunological factors were limiting the therapeutic efficacy of transplanted MSC-derived IPCs. Preconditioning MSCs with proinflammatory cytokines was proven to enhance their immunosuppressive capabilities. Yet, it remains unclear how cytokine stimulation influences the immunoregulatory features of theses differentiated IPCs. Therefore, we aimed to investigate the potential role of tumor necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ)–primed MSC-derived IPCs in inducing and regulating immunological tolerance. Methods: MSCs were isolated from human adipose tissue (hAT-MSCs) and differentiated into IPCs. Subsequently, the cells were assigned into five groups as follows: the control (hAT-MSCs) group, the differentiated (IPCs) group, the differentiated cells primed with IFN-γ (IPCs+ IFN-γ group), the differentiated cells primed with TNF-α (IPCs+ TNF-α group), the differentiated cells primed with both cytokines (IPCs+ Mix group). Flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were employed to detect the expression of immunomodulators, insulin/c-peptide, and pancreatic gene expression. Results: The results indicated that IPCs treated with both cytokines exhibited the highest expression of insulin/c-peptide and pancreatic genes, as well as the immune checkpoints programmed death ligand 1 (PD-L1) and kynurenine (KYN), which are immunosuppressants. Furthermore, IFN-γ priming also enhanced the expression of the immunological regulators: human leukocyte antigen class 1 (HLA-ABC) and class 2 (HLA-DR). Conclusions: Preconditioning IPCs with IFN-γ/TNF-α enhances their immunomodulatory profile through checkpoint molecules and insulin secretion, suggesting a novel immunological strategy for treating T1DM.</div> Cytokine Priming, Immunotolerance, Insulin-Producing Cells, Interferon-gamma (IFN-γ), Tumor necrosis factor-alpha (TNF-α). 155 170 http://rbmb.net/browse.php?a_code=A-10-1818-1&slc_lang=en&sid=1 Mohga Mohamed Al-issawi mohgaelissawi@std.mans.edu.eg 100319475328460022392 100319475328460022392 Yes Biotechnology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. Mahmoud Mohamed Gabr 100319475328460022393 100319475328460022393 No Biotechnology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. Sherry Mohamed Khater 100319475328460022394 100319475328460022394 No Pathology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt. Abdel-Aziz Abdel-Aziz 100319475328460022395 100319475328460022395 No Chemistry Department, Division of Biochemistry, Faculty of Sciences, Mansoura University, Mansoura, Egypt.