The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency

ST Schmid,¹ J Koepke,¹ M Dresel,¹ A Hattesohl,¹ E Frenzel,² J Perez,³ DA Lomas,⁴ E Miranda,⁵ T Greulich,¹ S Noeske,¹ M Wencker,⁶ H Teschler,⁶ C Vogelmeier,¹ S Janciauskiene,^2,* AR Koczulla<sup>1,*

1</sup>Department of Internal Medicine, Division for Pulmonary Diseases, University Hospital Marburg, Marburg, Germany; ²Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; ³Department of Cellular Biology, University of Malaga, Malaga, Spain; ⁴Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; ⁵Department of Biology and Biotechnology, Istituto Pasteur – Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; ⁶Department of Pneumology, West German Lung Clinic, Essen University Hospital, Essen, Germany

*These authors contributed equally to this work

Background: The major concept behind augmentation therapy with human α₁-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.
Objective: To evaluate the short-term effects of augmentation therapy (Prolastin®) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.
Materials and methods: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL).
Results: There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor- α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells.
Conclusion: Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.

Keywords: Prolastin, augmentation therapy, cytokines, IL-8, exhaled breath condensate, neutrophils