Alpha-1-Antitrypsin in Cell and Organ Transplantation.

Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti-inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation. Although traditionally considered an extracellular inhibitor of serine proteases, alpha-1-antitrypsin also has intracellular effects that may be beneficial in transplantation, including inhibiting apoptosis and NF-kB activation, modulating proversus anti-inflammatory cytokine balance, and promoting tolerance.