Table 1 Selected in vivo biological activities of AAT.
From: Expanding the Clinical Indications for α1-Antitrypsin Therapy
In vivo model | Source and dose of AAT | Outcomes | Reference |
|---|---|---|---|
Modulation of adaptive immunity | |||
Islet allograft immune response | Aralast, 60 mg/kg; matrigelembedded islets | Graft survival prolonged, immune cell infiltration reduced, intragraft insulin content increased, intragraft VEGF transcript levels elevated | |
Aralast, 60 mg/kg Plasmid-derived hAAT, 450 μg/mL plasma levels | Grafts accepted, immune tolerance achieved, Tregs localized at graft sites, systemic and local IL-1Ra elevated | ||
Islet autoimmune response | Aralast, 60 mg/kg; adeno-associated delivery of recombinant AAT | Islet function preserved, immune tolerance achieved, auto- and alloreactive grafts accepted | |
Cell allograft immune response | Aralast, 60 mg/kg | Day 1–5 immune cell infiltration reduced, including macrophages, neutrophils, T cells and NK cells | |
CIA | Prolastin, 60 mg/kg | Delayed disease onset, lower disease score | |
EAE | Mice transgenic for hAAT, constitutive 0.2 μg/mL plasma levels | Decreased disease incidence, lower disease score, increased Treg proportions in lymphoid compartments | |
GVHD (MHC disparate bone-marrow transplantation) | Aralast, 1–4 mg/dose | Attenuation (posttreatment) and prevention (pretreatment) of GVHD, reduced expansion of alloreactive T cells, enhanced recovery of Tregs, reduced serum levels of proinflammatory cytokines and superior survival | |
In vivo leukocyte infiltration | |||
ThG-elicited peritoneal infiltration | Aralast, 60 mg/kg | Infiltrating macrophages and neutrophils diminished | |
Acute myocardial infarction | Aralast, 60 mg/kg | Myocardial leukocyte infiltration diminished | |
EAE | Tissue-specific transgenic hAAT, 0.2 μg/mL plasma levels | Decreased spinal leukocytic infiltration | |
In vivo innate responses | |||
Systemic LPS challenge (mice) | hAAT plasmid-derived, 450 μg/mL plasma levels | Antiinflammatory serum cytokine profile, for example, elevated IL-1Ra and IL-10 and greater levels of foxp3 Tregs | |
Lung LPS challenge (rabbits) | hAAT Shanghai Biological Production Institute, 120 mg/kg | Lung function and arterial blood gases improved, bronchoalveolar neutrophil elastase, TNF-α and IL-8 reduced | |
In vivo cell injury | |||
Toxic β-cell injury | Aralast, 60 mg/kg | 48-h cell death reduced, insulin release preserved | |
Acute myocardial injury after LAD occlusion and myocardial infarction | Aralast, 60 mg/kg | Reduced infarct size, decreased caspase-1 tissue levels, reduced post-infarct remodeling |