ArticleThe Journal of clinical investigation2021
Calcineurin inhibitors suppress acute graft-versus-host disease via NFAT-independent inhibition of T cell receptor signaling.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 41 citations in OpenAlex.
- Anti-CD4 antibody-modulated transplants for GVHD prevention in hematopoietic cell transplantation.Blood · 2026Article
- CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators.Journal of neuroinflammation · 2026Article
- Pre-Administration of Akkermansia Muciniphila Prevents the Development of Severe Acute Graft-Versus-Host Disease in Systemic Organs.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Combination of B-cell-guided rituximab and low-dose tacrolimus for primary membranous nephropathy: a retrospective cohort study.Frontiers in medicine · 2026Article
- Case of Myelodysplastic Syndrome 15 Years After Kidney Transplantation Under Long-Term Immunosuppression.Case reports in hematology · 2026Article
- Calcineurin Inhibitors: Current Role, Toxicity Management, and Future Frontiers in Immunosuppression.Molecular neurobiology · 2025Review
- Recent advances in polymer-based drug delivery systems for atopic dermatitis: enhancing therapeutic efficacy and outcomes.Materials today. Bio · 2025Review
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- Genome-edited allogeneic CAR-T cells: the next generation of cancer immunotherapies.Journal of hematology & oncology · 2025Review
- Bibliometric and visual analysis of overlooked fatigue in kidney transplantation: a narrative review.Annals of medicine and surgery (2012) · 2025Review
- Managing allorejection in off-the-shelf CAR-engineered cell therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
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- Addressing graft-versus-host disease in allogeneic cell-based immunotherapy for cancer.Experimental hematology & oncology · 2025Review
- Exploring the tumor microenvironment of colorectal cancer patients post renal transplantation by single-cell analysis.Cancer science · 2025Article
- Graft-Versus-Host Disease Mouse Models: A Clinical-Translational Perspective.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Article
- Continuous immunosuppression is required for suppressing immune responses to xenografts in non-human primate brains.Cell regeneration (London, England) · 2024Article
- The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice.Pharmaceutics · 2023Article
- Nitro-oleic acid regulates T cell activation through post-translational modification of calcineurin.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Advances in dendritic cell targeting nano-delivery systems for induction of immune tolerance.Frontiers in bioengineering and biotechnology · 2023Review
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6 authors at 3 institutions in 3 countries.
Funding
Abstract
Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of gene expression dependent on nuclear factor of activated T cells (NFAT) is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express LckS59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either LckWT or LckS59A, it was ineffective in treating disease when the T cells expressed LckS59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in LckS59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8+ T cells and antigen-specific T/DC adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.