Alpha-1-antitrypsin in cell and organ transplantation

Abstract

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 30 years 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.

Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

“…AAT modulates both the activation and maturation of antigen-presenting cells [ 19 , 20 , 21 ], inhibition of various caspases, and improvement of the mitochondrial membrane stability [ 22 ]. Thus, AAT downregulates proinflammatory cytokines and upregulates anti-inflammatory mediators [ 19 , 21 , 23 ], with these properties, AAT attenuates tissue fibrosis and prevents apoptotic cell death [ 19 , 24 , 25 , 26 ]. The function of AAT has not yet been identified in TAC-induced nephrotoxicity; however, it has been verified in the present study.…”

Proteomic Identification of Plasma Biomarkers in Children and Adolescents with Recurrent Hodgkin Lymphoma

“…Of note, in NR an increase in an antithrombin-II (spot 259), a plasma cofactor that inactivates several coagulation factors, was also observed. The most noticeable activity of AAT is to limit inflammatory tissue damage, but accumulating evidences suggested new roles in tissue-protection such as in the improvement of mitochondrial membrane stability, inhibition of proinflammatory cytokine production, promotion of anti-tumor agents 11-12. Untreated individuals with genetic AAT deficiency are associated with elevated rates of liver malignancies 13, lung 14 and gastrointestinal 15 cancers, suggesting a protective role of AAT to cancer 16.…”

Hematopoietic Stem/Progenitor Cell Dependent Participation of Innate Lymphoid Cells in Low-Intensity Sterile Inflammation

“…Next, we sought to investigate whether a transient pharmacologic manipulation with alpha-1 anti-trypsin (AAT), an acute phase anti-inflammatory protein ( 25 – 27 ) can influence the presence, abundance, and phenotype of the recovered ILCs from the site of inflammation. Mice were injected i.p with low- or high-dose of zymosan and 15 min later they received an i.p injection with alpha-1 antitrypsin, a protein with well-known anti-inflammatory activity.…”