Xenorecognition and costimulation of porcine endothelium-derived extracellular vesicles in initiating human porcine-specific T cell immune responses.
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2023-07
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Porcine vascular endothelial cells (PECs) form a mechanistic centerpiece of xenograft rejection. Here, we determined that resting PECs release swine leukocyte antigen class I (SLA-I) but not swine leukocyte antigen class-II DR (SLA-DR) expressing extracellular vesicles (EVs) and investigated whether these EVs proficiently initiate xenoreactive T cell responses via direct xenorecognition and costimulation. Human T cells acquired SLA-I+ EVs with or without direct contact to PECs, and these EVs colocalized with T cell receptors. Although interferon gamma-activated PECs released SLA-DR+ EVs, the binding of SLA-DR+ EVs to T cells was sparse. Human T cells demonstrated low levels of proliferation without direct contact to PECs, but marked T cell proliferation was induced following exposure to EVs. EV-induced proliferation proceeded independent of monocytes/macrophages, suggesting that EVs delivered both a T cell receptor signal and costimulation. Costimulation blockade targeting B7, CD40L, or CD11a significantly reduced T cell proliferation to PEC-derived EVs. These findings indicate that endothelial-derived EVs can directly initiate T cell-mediated immune responses, and suggest that inhibiting the release of SLA-I EVs from organ xenografts has the potential to modify the xenograft rejection. We propose a secondary-direct pathway for T cell activation via xenoantigen recognition/costimulation by endothelial-derived EVs.
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Li, Shu, Imran J Anwar, Aidan J Canning, Tuan Vo-Dinh, Allan D Kirk and He Xu (2023). Xenorecognition and costimulation of porcine endothelium-derived extracellular vesicles in initiating human porcine-specific T cell immune responses. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 23(7). pp. 904–919. 10.1016/j.ajt.2023.04.006 Retrieved from https://hdl.handle.net/10161/31516.
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Scholars@Duke
Shu Li
Imran Anwar
Aidan Canning
Tuan Vo-Dinh
Dr. Tuan Vo-Dinh is R. Eugene and Susie E. Goodson Distinguished Professor of Biomedical Engineering, Professor of Chemistry, and Director of The Fitzpatrick Institute for Photonics.
Dr. Vo-Dinh’s research activities and interests involve biophotonics, nanophotonics, plasmonics, laser-excited luminescence spectroscopy, room temperature phosphorimetry, synchronous luminescence spectroscopy, and surface-enhanced Raman spectroscopy for multi-modality bioimaging, and theranostics (diagnostics and therapy) of diseases such as cancer and infectious diseases.
We have pioneered the development of a new generation of gene biosensing probes using surface-enhanced Raman scattering (SERS) detection with “Molecular Sentinels” and Plasmonic Coupling Interference (PCI) molecular probes for multiplex and label-free detection of nucleic acid biomarkers (DNA, mRNA, microRNA) in early detection of a wide variety of diseases.
In genomic and precision medicine, nucleic acid-based molecular diagnosis is of paramount importance with many advantages such as high specificity, high sensitivity, serotyping capability, and mutation detection. Using SERS-based plasmonic nanobiosensors and nanochips, we are developing novel nucleic acid detection methods that can be integrated into lab-on-a-chip systems for point-of-care diagnosis (e.g., breast, GI cancer) and global health applications (e.g., detection of malaria and dengue).
In bioimaging, we are developing a novel multifunctional gold nanostar (GNS) probe for use in multi-modality bioimaging in pre-operative scans with PET, MRI and CT, intraoperative margin delineation with optical imaging, SERS and two-photon luminescence (TPL). The GNS can be used also for cancer treatment with plasmonics enhanced photothermal therapy (PTT), thus providing an excellent platform for seamless diagnostics and therapy (i.e., theranostics). Preclinical studies have shown its great potential for cancer diagnostics and therapeutics for future clinical translation.
For fundamental studies, various nanobiosensors are being developed for monitoring intracellular parameters (e.g., pH) and biomolecular processes (e.g., apoptosis, caspases), opening the possibility for fundamental molecular biological research as well as biomedical applications (e.g., drug discovery) at the single cell level in a systems biology approach. For point of care diagnostics, nanoprobes and nanochips with highly multiplex SERS detection and imaging use artificial intelligence and machine learning for data analysis.
Our research activities in immunotherapy involve unique plasmonics-active gold “nanostars.” These star-shaped nanobodies made of gold work like “lightning rods,” concentrating the electromagnetic energy at their tips and allowing them to capture photon energy more efficiently when irradiated by laser light. Teaming with medical collaborators, we have developed a novel cancer treatment modality, called synergistic immuno photothermal nanotherapy (SYMPHONY), which combines immune-checkpoint inhibition and gold nanostar–mediated photothermal immunotherapy that can unleash the immunotherapeutic efficacy of checkpoint inhibitors. This combination treatment can eradicate the primary tumors as well as distant “untreated” tumors, and induce immunologic memory like a “anti-cancer vaccine” effect in murine model.
He Xu
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