By use of transgenic sheep that carry the genetic sequence for human α1
- antitrypsin (AAT) under the control of mammary gland promoter, biologically active human AAT has been generated in milk and purified and introduced to humans by intravenous infusion (1
). By using this method, it is estimated that a population of 4,500 sheep would be able to provide in a single year 5,000 kg (~11,000 lb) of human AAT. Unfortunately, the reaction of individuals who participated in the infusion trial was one of rapid onset of fever due to the mounting of human anti-sheep anti bodies against residual sheep α1
-antichymotrypsin. The trial was discontinued. The original goal of this endeavor was to provide sufficient AAT to treat an increasing number of patients who are diagnosed with low circulating levels of AAT. The current source of AAT for augmentation therapy is human plasma–derived affinity-purified AAT. Yet, whereas the purpose of augmentation therapy is to avoid the progression of lung emphysema, efficacy studies that assess this goal are incomplete (reviewed in [2
Parallel studies that examine various attributes of human AAT depict the molecule as more than just an antiprotease. AAT appears to effectively interfere with inflammatory responses and protect from cell death in an impressive variety of in vivo
() and in vitro
() experimental models (3
). A noteworthy example includes the blockade of inflammatory cytokine release from human peripheral blood mononuclear cells (PBMC) (4
). Specifically, AAT decreases the production of important inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, two prototypical upstream mediators of inflammation. AAT also lowers the levels of the chemokines IL-8 and monocyte chemotactic protein (MCP)-1, two major chemokines in the trafficking of inflammatory cells. Whereas the activity of proinflammatory cytokines appears to consistently diminish in the presence of elevated AAT, the release of antiinflammatory mediators increases. The endogenous inhibitor of IL-1 activity, IL-1 receptor antagonist, is upregulated by AAT in human blood cells (5
). Similarly, IL-10 levels have been shown to increase by AAT in various experimental conditions (4
). When examining the cellular targets of AAT, one finds that these primarily include members of the innate immune system, such as macrophages and neutrophils, as well as B lymphocytes and dendritic cells. In contrast, responses of purified T lymphocytes are consistently unaffected by AAT (7
), allowing for a variety of responses to IL-2, as well as to concanavalin A and anti-CD3/CD28 stimulation, to persist. This cell-specific discretion, together with the ability to protect tissues from injury, sets AAT in a unique niche among modulators of the immune system, a separate entity to other antiinflammatory agents and classic immunosuppressants.
Selected in vivo biological activities of AAT.
Selected in vitro biological activities of AAT.
As an acute-phase protein, AAT rises in the circulation approximately fourfold and remains elevated for a week to 10 d. These levels are reproduced clinically by so-called replacement or augmentation therapy, using affinity-purified human AAT (14
). The standard protocol involves lifelong weekly infusions that result in a typical profile of systemic AAT: a spike that reaches fourfold the normal values in the first half of the week and a decline toward background levels before the next weekly infusion is afforded. Administration of AAT under these parameters reveals both excellent patient safety and patient compliance (15
The attempts to generate transgenic sheep for producing human AAT and other methods for AAT mass production represent a longstanding effort to generate much AAT for individuals who suffer from genetic AAT deficiency. However, the case for human AAT therapy outside this particular indication appears to be stronger than ever. In this review, an update is provided on recent findings that relate to the ability of AAT to protect tissues as well as block unwanted inflammatory processes and modify the immune system in a beneficial and safe manner. According to the published studies presented above, one can readily appreciate that AAT has a potential benefit for an impressive broad spectrum of human diseases, reigniting the requirement for yet greater supplies of human plasma– derived AAT, human AAT generated by recombinant techniques or, at a minimum, biologically active AAT fragments.