Abstract
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.
Highlights
Lung transplantation (LuTx) is an established therapy for end-stage lung diseases
Scoring of allograft sections according to the international society of heart and lung transplantation (ISHLT) classification of acute rejection, which is the official guideline for the histopathological evaluation of human pulmonary grafts [28], revealed significant (p = 0.006) differences among allografts from recipients treated with vehicle (n = 5, median 3) and Alpha 1-antitrypsin (AAT) (n = 10, median 1; Fig. 3c)
Results from our model show that AAT therapy brings a different mechanism against acute LuTx rejection
Summary
Lung transplantation (LuTx) is an established therapy for end-stage lung diseases. In recent years the number of lung transplants has increased worldwide, and patient survival worldwide increased from a median of 4.3 years (1990–1998) to 6.5 years (2009–2016) [1]. Different studies reported that patients with BOS have diminished levels of Tregs, a subset of CD4+ T cells, and that the misbalance between Tregs and Th17 (a CD4+ T-cell subset producing interleukin-17) may predict a risk of developing BOS [6]. The prevention of acute lung rejection is one of the strategies against CLAD development. Because of a strong immune system of the lungs, the recipients after LuTx receive high doses of immune suppressions, especially calcineurin inhibitors [5], which may cause various complications, including damage of renal function, infections, and development of tumors [9, 10]. The development of new approaches weaning LuTx patients from immunosuppression are warranted
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