α1-Antitrypsin attenuates acute rejection of orthotopic murine lung allografts

Respiratory Research

Tobias Goecke¹  Fabio Ius¹  Ann-Kathrin Knöfel¹  Tomoyuki Nakagiri¹  Patrick Zardo²  Axel Haverich²  Veronika Grau³  Kokilavani Sivaraman⁴  Sabine Wrenger⁴  Sabina Janciauskiene⁵  Tobias Welte⁵ 

[1] Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany;Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany;Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany;Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University Giessen, German Center for Lung Research, Giessen, Germany;Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany;Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany;Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany;

关键词: Lung transplantation;    Acute allograft rejection;    Mouse orthotopic single lung transplantation model;    Primary graft dysfunction;    Alpha1-antitrypsin;   

DOI  :  10.1186/s12931-021-01890-x

来源: Springer

【 摘 要 】

Backgroundα1-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.MethodsWe 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.ResultsHistological 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.ConclusionTherapy 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.

【 授权许可】

CC BY