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Adenosine triphosphate-mediated signaling of P2X7 receptors controls donor extracellular vesicle release and major histocompatibility complex cross-decoration after allotransplantation.
Am J Transplant
December 2024
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address:
After skin allotransplantation, intercellular transfer of donor major histocompatibility complex molecules mediated primarily by extracellular vesicles (EVs) released by the allograft is known to contribute to semidirect and indirect activation of alloreactive T cells involved in graft rejection. At the same time, there is ample evidence showing that initiation of adaptive alloimmunity depends on early innate inflammation caused by tissue injury and subsequent activation of myeloid cells (macrophages and dendritic cells) recognizing danger-associated molecular patterns. Among these danger-associated molecular patterns, extracellular adenosine triphosphate plays a key role in innate inflammation by binding to P2X7 receptors (P2X7Rs).
View Article and Find Full Text PDFHypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses.
J Immunol
December 2024
Beam Therapeutics, Cambridge, MA.
Article Synopsis
- Chimeric antigen receptor (CAR) T cells from universal donors can be rejected by the recipient's immune system, which impacts their effectiveness and longevity in treatment.
- The researchers created HLA class I-deficient T cells to avoid detection by mismatched CD8+ T cells and improved their NK cell tolerance using a specially designed molecule called dtHLA-E4.
- The optimized dtHLA-E4 molecule showed better surface expression, enhanced NK cell inhibition, and reduced recognition by CD8+ T cells while maintaining the ability to inhibit NK cells, making it a promising strategy for improving the persistence of CAR T cells in treatment.
Immunomodulation of T cell-mediated alloimmunity by proximity to endothelial cells under the mammalian target of rapamycin blockade.
Am J Transplant
October 2024
Division of Transplant and Immunobiology Research, Departments of Surgery, Duke University School of Medicine, Durham, North Carolina, USA; Departments of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs.
View Article and Find Full Text PDFRapamycin Prevents Expansion of Costimulation Blockade-resistant CD8+ Alloreactive Memory Cells following Depletional Induction in Renal Transplant Recipients.
J Immunol
November 2024
Department of Surgery, Duke University School of Medicine, Durham, NC.
Alemtuzumab induction with belatacept/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade-resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7-induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells.
View Article and Find Full Text PDFCD19-chimeric antigen receptor-invariant natural killer T cells transactivate NK cells and reduce alloreactivity.
Cytotherapy
January 2025
Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany; Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland. Electronic address:
Invariant natural killer T (iNKT) cells are a small fraction of T lymphocytes with strong cytotoxic and immunoregulatory properties. We previously showed that human culture-expanded iNKT cells prevent alloreactivity and lyse primary leukemia blasts. Here, iNKT cells have several advantages over T cells based on their immunoregulatory capabilities.
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