Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance

Article


Smyth, L., Meader, Lucy, Xiao, Fang, Woodward, Martin, Brady, Hugh J., Lechler, Robert and Lombardi, Giovanna 2017. Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance. Clinical and Experimental Immunology. 188 (2), pp. 219-225.
AuthorsSmyth, L., Meader, Lucy, Xiao, Fang, Woodward, Martin, Brady, Hugh J., Lechler, Robert and Lombardi, Giovanna
Abstract

Anti-apoptotic genes including those of the Bcl-2 family have been shown to have dual functionality in as much as they inhibit cell death but also regulate inflammation. Several anti-apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation however their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl-1), a Bcl-2 family member, under the control of the human ICAM-2 promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the pro-inflammatory cytokine TNF-α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8+ T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which maybe related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti-apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.

Keywordsendothelial; anti-apoptotic
JournalClinical and Experimental Immunology
Journal citation188 (2), pp. 219-225
ISSN0009-9104
1365-2249
Year2017
PublisherWiley for British Society for Immunology
Accepted author manuscript
License
Digital Object Identifier (DOI)doi:10.1111/cei.12931
Web address (URL)http://doi.org/10.1111/cei.12931
Publication dates
Print24 Jan 2017
Publication process dates
Deposited02 Mar 2017
Accepted06 Jan 2017
FunderBritish Heart Foundation
National Institute for Health Research (NIHR)
Guy's and Thomas’ NHS Foundation Trust
King's College London
British Heart Foundation
National Institute for Health Research
Guy's and St Thomas' NHS Foundation Trust
King's College London
Copyright informationThis is the peer reviewed version of the following article: Smyth, L. A., Meader, L., Xiao, F., Woodward, M., Brady, H. J., Lechler, R. and Lombardi, G. (2017), Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance, Clinical and Experimental Immunology, which has been published in final form at doi:10.1111/cei.12931. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Permalink -

https://repository.uel.ac.uk/item/84x58

  • 7
    total views
  • 53
    total downloads
  • 2
    views this month
  • 3
    downloads this month

Related outputs

Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances
Hassan, Hatem A.F.M., Diebold, Sandra S., Smyth, L., Walters, Adam A., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2019. Application of carbon nanotubes in cancer vaccines: Achievements, challenges and chances. Journal of Controlled Release. 297, pp. 79-90.
Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function
Peng, Q., Ratnasothy, K., Boardman, D. A., Jacob, J., Tung, S. T., McCluskey, D., Smyth, L., Lechler, R. I., Dorling, A. and Lombardi, G. 2019. Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function. Frontiers in Immunology. 10 (Art. 1311).
Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice – a novel and universal approach
Faruqu, Farid N., Wang, Julie Tzu-Wen, Xu, Lizhou, McNickle, Luke, Chong, Eden Ming-Yiu, Walters, Adam, Gurney, Mark, Clayton, Aled, Smyth, L., Hider, Robert, Sosabowski, Jane and Al-Jamal, Khuloud T. 2019. Membrane radiolabelling of exosomes for comparative biodistribution analysis in immunocompetent and immunodeficient mice – a novel and universal approach. Theranostics. 9 (6), pp. 1666-1682.
Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling
Emmerson, Amber, Trevelin, Silvia Cellone, Mongue-Din, Heloise, Becker, Pablo D., Ortiz, Carla, Smyth, L., Peng, Qi, Elgueta, Raul, Sawyer, Greta, Ivetic, Aleksandar, Lechler, Robert I., Lombardi, Giovanna and Shah, Ajay M. 2018. Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling. Journal of Clinical Investigation. 128 (7), pp. 3088-3101.
Regulatory T cell-derived extracellular vesicles modify dendritic cell function
Tung, Sim L., Boardman, Dominic A., Sen, Monica, Letizia, Marilena, Peng, Qi, Cianci, Nicole, Dioni, Laura, Carlin, Leo M., Lechler, Robert, Bollati, Valentina, Lombardi, Giovanna and Smyth, L. 2018. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Scientific Reports. 8, p. 6065.
Galectin-1 is required for the regulatory function of B cells
Alhabbab, R., Blair, P., Smyth, L., Ratnasothy, K., Peng, Q., Moreau, A., Lechler, R., Elgueta, R. and Lombardi, G. 2018. Galectin-1 is required for the regulatory function of B cells. Scientific Reports. 8 (2725).
Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy
Hassan, Hatem A.F.M., Smyth, L., Wang, Julie T.-W., Costa, Pedro M., Ratnasothy, Kulachelvy, Diebold, Sandra S., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2016. Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy. Biomaterials. 104, pp. 310-322.
Regulatory T Cell-Derived Exosomes: Possible Therapeutic and Diagnostic Tools in Transplantation
Agarwal, Akansha, Fanelli, Giorgia, Letizia, Marilena, Tung, Sim Lai, Boardman, Dominic, Lechler, Robert, Lombardi, Giovanna and Smyth, L. 2014. Regulatory T Cell-Derived Exosomes: Possible Therapeutic and Diagnostic Tools in Transplantation. Frontiers in Immunology. 5.
UK–Russia Researcher Links Workshop: extracellular vesicles – mechanisms of biogenesis and roles in disease pathogenesis, M.V. Lomonosov Moscow State University, Moscow, Russia, 1–5 March 2015
Kapustin, Alexander N., Kalinina, Natalia, Lopatina, Tatiana, Davidson, Sean M., Iraci, Nunzio, Tamkovich, Svetlana, Smyth, L., Ter-Ovanesyan, Dmitry, Evtushenko, Evgeniy G., Savelieva, Olga, Bertazzo, Sergio, Aushev, Vassiliy, Dragovic, Rebecca, Gracia, Tannia, Heck, Margarete, Parfyonova, Yelena V., Shanahan, Catherine M. and Tkachuk, Vsevolod 2015. UK–Russia Researcher Links Workshop: extracellular vesicles – mechanisms of biogenesis and roles in disease pathogenesis, M.V. Lomonosov Moscow State University, Moscow, Russia, 1–5 March 2015. Journal of Extracellular Vesicles. 4 (1), p. 28094.
Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model
Alhabbab, R., Blair, P., Elgueta, R., Stolarczyk, E., Marks, E., Becker, P. D., Ratnasothy, K., Smyth, L., Safinia, N., Sharif-Paghaleh, E., O’Connell, S., Noelle, R. J., Lord, G. M., Howard, J. K., Spencer, J., Lechler, R. I. and Lombardi, G. 2015. Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model. Scientific Reports. 5, p. 11554.
Carbon nanotubes' surface chemistry determines their potency as vaccine nanocarriers in vitro and in vivo
Hassan, Hatem A.F.M., Smyth, L., Rubio, Noelia, Ratnasothy, Kulachelvy, Wang, Julie T.-W., Bansal, Sukhvinder S., Summers, Huw D., Diebold, Sandra S., Lombardi, Giovanna and Al-Jamal, Khuloud T. 2016. Carbon nanotubes' surface chemistry determines their potency as vaccine nanocarriers in vitro and in vivo. Journal of Controlled Release. 225, pp. 205-216.
Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+T cell immunity
Smyth, L., Lechler, Robert I and Lombardi, Giovanna 2016. Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+T cell immunity. American Journal of Transplantation. 17 (1), pp. 60-68.
What Is Direct Allorecognition?
Boardman, Dominic A., Jacob, Jacinta, Smyth, L., Lombardi, Giovanna and Lechler, Robert I. 2016. What Is Direct Allorecognition? Current Transplantation Reports. 3 (4), pp. 275-283.
Treg therapy in transplantation a general overview
Romano, Marco, Tung, Sim Lai, Smyth, L. and Lombardi, Giovanna 2016. Treg therapy in transplantation a general overview. Transplant International. 30 (8), pp. 745-753.
Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection
Boardman, Dominic A., Philippeos, Christina, Fruhwirth, Gilbert O., Ibrahim, Mohammad A. A., Hannen, Rosalind F., Cooper, Dianne, Marelli-Berg, Federica M., Watt, Fiona M., Lechler, Robert I., Maher, John, Smyth, L. and Lombardi, Giovanna 2016. Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. American Journal of Transplantation. 17 (4), pp. 931-943.