α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts
Abstract Background α1-Antitrypsin (AAT) is an acute phase glycoprotein, a multifunctional protein with proteinase inhibitory, anti-inflammatory and cytoprotective properties. Both preclinical and clinical experiences show that the therapy with plasma purified AAT is beneficial for a broad spectrum...
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2021
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oai:doaj.org-article:81338e3554414e0a80aaf3bb0be142c32021-11-21T12:31:56Zα1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts10.1186/s12931-021-01890-x1465-993Xhttps://doaj.org/article/81338e3554414e0a80aaf3bb0be142c32021-11-01T00:00:00Zhttps://doi.org/10.1186/s12931-021-01890-xhttps://doaj.org/toc/1465-993XAbstract Background α1-Antitrypsin (AAT) is an acute phase glycoprotein, a multifunctional protein with proteinase inhibitory, anti-inflammatory and cytoprotective properties. Both preclinical and clinical experiences show that the therapy with plasma purified AAT is beneficial for a broad spectrum of inflammatory conditions. The potential effects of AAT therapy have recently been highlighted in lung transplantation (LuTx) as well. Methods We used a murine fully mismatched orthotopic single LuTx model (BALB/CJ as donors and C57BL/6 as recipients). Human AAT preparations (5 mg, n = 10) or vehicle (n = 5) were injected to the recipients subcutaneously prior to and intraperitoneally immediately after the LuTx. No immune suppressive drugs were administered. Three days after the transplantation, the mice were sacrificed, and biological samples were assessed. Results Histological analysis revealed significantly more severe acute rejection in the transplanted lungs of controls than in AAT treated mice (p < 0.05). The proportion of neutrophil granulocytes, B cells and the total T helper cell populations did not differ between two groups. There was no significant difference in serum CXCL1 (KC) levels. However, when compared to controls, human AAT was detectable in the serum of mice treated with AAT and these mice had a higher serum anti-elastase activity, and significantly lower proportion of Th1 and Th17 among all Th cells. Cleaved caspase-3-positive cells were scarce but significantly less abundant in allografts from recipients treated with AAT as compared to those treated with vehicle. Conclusion Therapy with AAT suppresses the acute rejection after LuTx in a mouse model. The beneficial effects seem to involve anti-protease and immunomodulatory activities of AAT.Tomoyuki NakagiriSabine WrengerKokilavani SivaramanFabio IusTobias GoeckePatrick ZardoVeronika GrauTobias WelteAxel HaverichAnn-Kathrin KnöfelSabina JanciauskieneBMCarticleLung transplantationAcute allograft rejectionMouse orthotopic single lung transplantation modelPrimary graft dysfunctionAlpha1-antitrypsinDiseases of the respiratory systemRC705-779ENRespiratory Research, Vol 22, Iss 1, Pp 1-12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Lung transplantation Acute allograft rejection Mouse orthotopic single lung transplantation model Primary graft dysfunction Alpha1-antitrypsin Diseases of the respiratory system RC705-779 |
| spellingShingle |
Lung transplantation Acute allograft rejection Mouse orthotopic single lung transplantation model Primary graft dysfunction Alpha1-antitrypsin Diseases of the respiratory system RC705-779 Tomoyuki Nakagiri Sabine Wrenger Kokilavani Sivaraman Fabio Ius Tobias Goecke Patrick Zardo Veronika Grau Tobias Welte Axel Haverich Ann-Kathrin Knöfel Sabina Janciauskiene α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| description |
Abstract Background α1-Antitrypsin (AAT) is an acute phase glycoprotein, a multifunctional protein with proteinase inhibitory, anti-inflammatory and cytoprotective properties. Both preclinical and clinical experiences show that the therapy with plasma purified AAT is beneficial for a broad spectrum of inflammatory conditions. The potential effects of AAT therapy have recently been highlighted in lung transplantation (LuTx) as well. Methods We used a murine fully mismatched orthotopic single LuTx model (BALB/CJ as donors and C57BL/6 as recipients). Human AAT preparations (5 mg, n = 10) or vehicle (n = 5) were injected to the recipients subcutaneously prior to and intraperitoneally immediately after the LuTx. No immune suppressive drugs were administered. Three days after the transplantation, the mice were sacrificed, and biological samples were assessed. Results Histological analysis revealed significantly more severe acute rejection in the transplanted lungs of controls than in AAT treated mice (p < 0.05). The proportion of neutrophil granulocytes, B cells and the total T helper cell populations did not differ between two groups. There was no significant difference in serum CXCL1 (KC) levels. However, when compared to controls, human AAT was detectable in the serum of mice treated with AAT and these mice had a higher serum anti-elastase activity, and significantly lower proportion of Th1 and Th17 among all Th cells. Cleaved caspase-3-positive cells were scarce but significantly less abundant in allografts from recipients treated with AAT as compared to those treated with vehicle. Conclusion Therapy with AAT suppresses the acute rejection after LuTx in a mouse model. The beneficial effects seem to involve anti-protease and immunomodulatory activities of AAT. |
| format |
article |
| author |
Tomoyuki Nakagiri Sabine Wrenger Kokilavani Sivaraman Fabio Ius Tobias Goecke Patrick Zardo Veronika Grau Tobias Welte Axel Haverich Ann-Kathrin Knöfel Sabina Janciauskiene |
| author_facet |
Tomoyuki Nakagiri Sabine Wrenger Kokilavani Sivaraman Fabio Ius Tobias Goecke Patrick Zardo Veronika Grau Tobias Welte Axel Haverich Ann-Kathrin Knöfel Sabina Janciauskiene |
| author_sort |
Tomoyuki Nakagiri |
| title |
α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| title_short |
α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| title_full |
α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| title_fullStr |
α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| title_full_unstemmed |
α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| title_sort |
α1-antitrypsin attenuates acute rejection of orthotopic murine lung allografts |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/81338e3554414e0a80aaf3bb0be142c3 |
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