ArticleBiology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation2014
IL-12hi rapamycin-conditioned dendritic cells mediate IFN-γ-dependent apoptosis of alloreactive CD4+ T cells in vitro and reduce lethal graft-versus-host disease.
Article in Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Possible Mechanisms of Lymphopenia in Severe Tuberculosis.Microorganisms · 2023Review
- Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms.Archivum immunologiae et therapiae experimentalis · 2021Article
- Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies.International journal of molecular sciences · 2021Review
- Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury.International journal of molecular sciences · 2021Article
- Innate Immune Determinants of Graft-Versus-Host Disease and Bidirectional Immune Tolerance in Allogeneic Transplantation.OBM transplantation · 2019Article
- Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells.JCI insight · 2018Article
- Protein dysregulation in graft versus host disease.Oncotarget · 2018Review
- Regulation of Dendritic Cell Immune Function and Metabolism by Cellular Nutrient Sensor Mammalian Target of Rapamycin (mTOR).Frontiers in immunology · 2018Review
- Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3Journal of immunology research · 2018Article
- Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.Blood · 2016Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4(+) forkhead box p3 (FoxP3(+)) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-γ(+) CD4(+) T cells. However, IFN-γ is pro-apoptotic and IL-12-driven IFN-γ inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12(hi) RAPA-DC would facilitate IFN-γ-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86(lo) IL-12(hi) cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4(+) T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-γ neutralization or using T cells lacking the IFN-γ receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-γ were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40(-/-) RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-γ. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4(+) T cells induced by LPS-stimulated IL-12(hi) RAPA-DC is mediated in vitro through IFN-γ and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-γ by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.
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