Engineering pancreatic islets with a novel form of thrombomodulin protein to overcome early graft loss triggered by instant blood-mediated inflammatory reaction.
In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jg. 23 (2023-05-01), Heft 5, S. 619-628
Online
academicJournal
Zugriff:
The instant blood-mediated inflammatory reaction (IBMIR) is initiated by innate immune responses that cause substantial islet loss after intraportal transplantation. Thrombomodulin (TM) is a multifaceted innate immune modulator. In this study, we report the generation of a chimeric form of thrombomodulin with streptavidin (SA-TM) for transient display on the surface of islets modified with biotin to mitigate IBMIR. SA-TM protein expressed in insect cells showed the expected structural and functional features. SA-TM converted protein C into activated protein C, blocked phagocytosis of xenogeneic cells by mouse macrophages and inhibited neutrophil activation. SA-TM was effectively displayed on the surface of biotinylated islets without a negative effect on their viability or function. Islets engineered with SA-TM showed improved engraftment and established euglycemia in 83% of diabetic recipients when compared with 29% of recipients transplanted with SA-engineered islets as control in a syngeneic minimal mass intraportal transplantation model. Enhanced engraftment and function of SA-TM-engineered islets were associated with the inhibition of intragraft proinflammatory innate cellular and soluble mediators of IBMIR, such as macrophages, neutrophils, high-mobility group box 1, tissue factor, macrophage chemoattractant protein-1, interleukin-1β, interleukin-6, tumor necrosis factor-α, interferon-γ. Transient display of SA-TM protein on the islet surface to modulate innate immune responses causing islet graft destruction has clinical potential for autologous and allogeneic islet transplantation.
(Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
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Engineering pancreatic islets with a novel form of thrombomodulin protein to overcome early graft loss triggered by instant blood-mediated inflammatory reaction.
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Autor/in / Beteiligte Person: | Turan, A ; Zhang, L ; Tarique, M ; Ulker, V ; Arguc, FN ; Badal, D ; Yolcu, ES ; Shirwan, H |
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Zeitschrift: | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jg. 23 (2023-05-01), Heft 5, S. 619-628 |
Veröffentlichung: | 2023- : [New York] : Elsevier ; <i>Original Publication</i>: Copenhagen : Munksgaard International Publishers, 2001-, 2023 |
Medientyp: | academicJournal |
ISSN: | 1600-6143 (electronic) |
DOI: | 10.1016/j.ajt.2023.02.021 |
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