DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival.

Autor:	Harrison DK; Division of Surgical Research, University of Arkansas for Medical Sciences, Little Rock, AR.; Center for Translational Pediatric Research, Arkansas Children's Research Institute, Little Rock, AR., Waldrip ZJ; Division of Surgical Research, University of Arkansas for Medical Sciences, Little Rock, AR.; Center for Translational Pediatric Research, Arkansas Children's Research Institute, Little Rock, AR., Burdine L; Division of Surgical Research, University of Arkansas for Medical Sciences, Little Rock, AR.; Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR., Shalin SC; Department of Pathology and Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR., Burdine MS; Division of Surgical Research, University of Arkansas for Medical Sciences, Little Rock, AR.; Center for Translational Pediatric Research, Arkansas Children's Research Institute, Little Rock, AR.
Jazyk:	angličtina
Zdroj:	Transplantation [Transplantation] 2021 Mar 01; Vol. 105 (3), pp. 540-549.
DOI:	10.1097/TP.0000000000003442
Abstrakt:	Background: Organ transplantation is life-saving and continued investigations into immunologic mechanisms that drive organ rejection are needed to improve immunosuppression therapies and prevent graft failure. DNA-dependent protein kinase catalytic subunit, DNA dependent-protein kinase catalytic subunit (DNA-PKcs), is a critical component of both the cellular and humoral immune responses. In this study, we investigate the contribution of DNA-PKcs to allogeneic skin graft rejection to potentially highlight a novel strategy for inhibiting transplant rejection. Methods: Fully MHC mismatched murine allogeneic skin graft studies were performed by transplanting skin from BalbC mice to C57bl6 mice and treating with either vehicle or the DNA-PKcs inhibitor NU7441. Graft rejection, cytokine production, immune cell infiltration, and donor-specific antibody formation were analyzed. Results: DNA-PKcs inhibition significantly reduced necrosis and extended graft survival compared with controls (mean survival 14 d versus 9 d, respectively). Inhibition reduced the production of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ and the infiltration of CD3+ lymphocytes into grafts. Furthermore, DNA-PKcs inhibition reduced the number of CD19+ B cells and CD19+ CD138+ plasma cells coinciding with a significant reduction in donor-specific antibodies. At a molecular level, we determined that the immunosuppressive effects of DNA-PKcs inhibition were mediated, in part, via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling through reduced expression of the p65 subunit. Conclusions: Our data confirm that DNA-PKcs contributes to allogeneic graft rejection and highlight a novel immunologic function for DNA-PKcs in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells and concomitant cytokine production. Competing Interests: The authors declare no conflicts of interest. (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu