Immune tolerance

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Abstract
This study investigated the tolerance induction and disruption of immune tolerance as strategies for immune modulation. For induction of immune tolerance, novel monocyte-derived tolerogenic dendritic cells (ItolDCs) were generated, and their ability to modulate the immune system was assessed using in vitro assays in hemophilia A patients who had developed neutralizing antibodies against their factor VIII replacement therapy. The cells were characterized, their functionality was assessed, and their feasibility as a safe cell therapy was further evaluated using both in vitro and in vivo studies for the induction of immune tolerance against factor VIII. For research on disruption of immune tolerance, meningioma, the most common brain tumor, was studied. To map the immune cell composition in meningiomas, a protocol was optimized for shorter enzymatic digestion, which breaks down the tissue into single-cell suspensions of viable immune cells. Since CD8+ T cells are vital in tumor suppression, further studies were conducted to explore their characteristics and identify possible targetable processes for immunotherapy. To investigate both induction and disruption of immune tolerance, various techniques were employed, including flow cytometry, immunohistochemistry, and functional-cell-based assays. Our investigation demonstrated that ItolDCs are a feasible and safe option for cell therapy aimed at inducing immune tolerance. Thus, factor VIII-loaded ItolDCs are ready for clinical evaluation to reduce inhibitor levels in patients with hemophilia A. Several tolerance-associated markers (PD-1, TIM-3, TIGIT, and LAG-3) were identified in CD8+ T cells in meningioma. These findings highlight how tumor cells may evade immune defenses and suggest potential immunotherapeutic targets, including immune checkpoint inhibitors. Taken together, various approaches may be employed for immune modulations to either induce or disrupt immune tolerance.

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