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A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.
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http://dx.doi.org/10.1172/JCI159925 | DOI Listing |
Front Cell Infect Microbiol
December 2024
Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity.
View Article and Find Full Text PDFMol Biotechnol
December 2024
Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan.
The immune system comprises various regulators and effectors that elicit immune responses against various attacks on the body. The pathogenesis of autoimmune diseases is derived from the deregulated expression of cytokines, the major regulators of the immune system. Among cytokines, interleukins have a major influence on immune-mediated diseases.
View Article and Find Full Text PDFBackground: Immune checkpoint inhibitors (ICIs) have revolutionised oncology care, by enhancing the body's T cell lymphocyte response against tumour cells. ICIs block the inhibitory signalling between tumour cells and the immune system, but consequently reduce immunological tolerance. Subsequently for some, this leads to immune-related adverse events (irAE), a spectrum term for autoimmune-like toxicities induced by ICIs that affects various tissues and organs.
View Article and Find Full Text PDFChem Biodivers
December 2024
Changzhou University - Wujin Campus: Changzhou University, School of Pharmacy & School of Biological and Food Engineerin, No. 21, Middle Lake Road, Wujin District, Changzhou City, Jiangsu Province, 213164, Changzhou, CHINA.
Deep mucosal and organ infections caused by the infestation of Candida albicans(C.albicans) in immunocompromised patients represent a significant cause of mortality in hospitalised patients. The rise in fungal resistance is a consequence of the overuse of antibiotics.
View Article and Find Full Text PDFBiol Open
December 2024
Research Center for Integrative Evolutionary Science, SOKENDAI 240-0193 Shonan Village, Hayama, Kanagawa, Japan.
We are naturally chimeras. Apart from our own cells originating from the fertilized egg, placental mammals receive small numbers of maternal cells called maternal microchimerism (MMc) that persist throughout one's whole life. Not only are varying frequencies of MMc cells reported in seemingly contradicting phenomena, including immune tolerance and possible contribution to autoimmune-like disease, but frequencies are observable even among healthy littermates showing varying MMc frequencies and cell type repertoire.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!